Synthesis of cycloalkyl substituted purine nucleosides via a metal-free radical route

Wang, Dongchao; Ran, Xia; Xie, Ming‐Sheng; Qu, Gui‐Rong; Guo, Hai‐Ming

doi:10.1039/c6ob00596a

Cited by 31 publications

(8 citation statements)

References 38 publications

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“…Purine derivatives are bases found in DNA and RNA, and they also possess antiviral activity 40–42 . There are three types of C(sp 2 )–H bonds, at C2, C6, and C8 in purines, and they are the cause of regioselectivity issues 43 . After much effort, conditions for the coupling of the hydroxamide ( 1a ) with 9-benzyl-9 H -purine ( 2a ) were successfully established.…”

Section: Resultsmentioning

confidence: 99%

Site-selective remote C(sp3)–H heteroarylation of amides via organic photoredox catalysis

Chen¹,

Fan²,

Yuan³

et al. 2019

Nat Commun

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Radical translocation processes triggered by nitrogen-centered radicals (NCRs), such as 1,5-hydrogen atom transfers (1,5-HAT), demonstrated by the well-established Hofmann-Löffler-Freytag (HLF) reaction, provide an attractive approach for the controllable and selective functionalization of remote inert C(sp3)–H bonds. Here we report an amidyl radical-triggered site-selective remote C(sp3)–H heteroarylation of amides under organic photoredox conditions. This approach provides a mild and highly regioselective reaction affording remote C(sp3)–H heteroarylated amides at room temperature under transition-metal free, weakly basic, and redox-neutral conditions. Non-prefunctionalized heteroarenes, such as purines, thiazolopyridines, benzoxazole, benzothiazoles, benzothiophene, benzofuran, thiazoles and quinoxalines, can be alkylated directly. Sequential and orthogonal C–H functionalization of different heteroarenes by taking advantage pH value or polarity of radicals has also been achieved. DFT calculations explain and can predict the site-selectivity and reactivity of this reaction. This strategy expands the scope of the Minisci reaction and serves as its alternative and potential complement.

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Section: Resultsmentioning

confidence: 99%

Site-selective remote C(sp3)–H heteroarylation of amides via organic photoredox catalysis

Chen¹,

Fan²,

Yuan³

et al. 2019

Nat Commun

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“…As is generally known, purine consists of an electron-deficient pyrimidine and an electron-rich imidazole partner ( Scheme 1 d). In other previous work and our own work, when purines were exposed to nucleophilic reagents such as Grignard reagents [ 17 , 18 , 19 , 20 ] and nucleophilic radical agents (Minisci reaction) [ 21 , 22 , 23 , 24 , 25 , 26 ], the regioselectivity of the reaction predominantly lay at the electron-deficient 6-position [ 12 , 13 , 14 , 15 , 16 ]. In contrast, when the electrophilic bromine was introduced, a C 8 -brominated purine derivative was obtained ( Scheme 1 c).…”

Section: Introductionmentioning

confidence: 99%

Direct Regioselective C-H Cyanation of Purines

Hu²,

Fu³

et al. 2023

Molecules

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A direct regioselective C-H cyanation of purines was developed through a sequential triflic anhydride activation, nucleophilic cyanation with TMSCN, followed by a process of base-mediated elimination of triflous acid (CF3SO2H). In most cases, the direct C-H cyanation occurred on the electron-rich imidazole motif of purines, affording 8-cyanated purine derivatives in moderate to excellent yields. Various functional groups, including allyl, alkynyl, ketone, ester, nitro et al. were tolerated and acted as a C8 directing group. The electron-donating 6-diethylamino, as C2-directing group substituent, can switch the regioselectivity of purine from 8- to 2-position, enabling the synthesis of 8- and 2-cyano 6-dialkylaminopurines from corresponding 6-chloropurine in different reaction order. Further functional manipulations of the cyano group allow the conversions of 8-cyanopurines to corresponding purine amides, imidates, imidothioates, imidamides, oxazolines, and isothiazoles.

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“…Nevertheless, some of these reactions usually had to face multifarious limitations caused by metal catalysts or coupling reagents, such as expensive metal catalysts, anhydrous condition, protecting groups, N 2 protection, multialkylation problems. To overcome the metal catalyst limitation, Guo et al successfully developed a metal‐free radical approach to synthesize C 6 ‐alkyl purine nucleosides induced by di‐tert‐butyl peroxide (DTBP) at 140°C [11]. However, only cycloalkanes that act as cosolvents were suitable and was still plagued by the C 6 , C 8 ‐dialkylation problem (Scheme 1B).…”

Section: Introductionmentioning

confidence: 99%

Light, metal‐free regioselectiveC⁶‐Halkylation of purines and purine nucleosides with alcohols

Liu

Sun

Tian

et al. 2023

Journal of Heterocyclic Chem

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A metal‐, light‐free radical alkylation reaction of purines and nucleosides has been achieved with readily available alcohols (1°, 2°, 3°) as the alkyl radical sources enabled by oxalates, which does not need any catalysts, N2 protection, and protecting groups. Although there are three potential active C(sp2)H bonds and four interferential nitrogen atoms in the purine motif, the reaction still shows excellent regioselectivity at C6H position and does not face multialkylation problem. Besides, this approach shows broad functional groups tolerance and is scalable to the gram level, which can be applied to late‐stage CH alkylation of purine to synthesize 6‐cyclopentyl nebularine with anti‐CEM activity, thus demonstrating its utility.

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Synthesis of cycloalkyl substituted purine nucleosides via a metal-free radical route

Cited by 31 publications

References 38 publications

Site-selective remote C(sp3)–H heteroarylation of amides via organic photoredox catalysis

Site-selective remote C(sp3)–H heteroarylation of amides via organic photoredox catalysis

Direct Regioselective C-H Cyanation of Purines

Light, metal‐free regioselectiveC⁶‐Halkylation of purines and purine nucleosides with alcohols

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Synthesis of cycloalkyl substituted purine nucleosides via a metal-free radical route

Cited by 31 publications

References 38 publications

Site-selective remote C(sp3)–H heteroarylation of amides via organic photoredox catalysis

Site-selective remote C(sp3)–H heteroarylation of amides via organic photoredox catalysis

Direct Regioselective C-H Cyanation of Purines

Light, metal‐free regioselectiveC6‐Halkylation of purines and purine nucleosides with alcohols

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Light, metal‐free regioselectiveC⁶‐Halkylation of purines and purine nucleosides with alcohols