Photocatalytic Alkylation of Pyrroles and Indoles with α-Diazo Esters

Ciszewski, Łukasz; Durka, Jakub; Gryko, Dorota

doi:10.1021/acs.orglett.9b02612

Cited by 100 publications

(60 citation statements)

References 36 publications

(25 reference statements)

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“…The observation of comparable levels of regioselectivity in the addition of diazoacetate derivatives would represent a major improvement over current aromatic C−H functionalization methodologies utilizing metallocarbene/carbene intermediates (Scheme ). Such a reaction would also be mechanistically distinct from recent work published by Gryko and co‐workers that relies on the generation and alkylation of alpha‐keto radicals from diazoacetate derivatives by using photoredox catalysis …”

Section: Methodsmentioning

confidence: 90%

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

2020

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Expanding the toolbox of C−H functionalization reactions applicable to the late‐stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition‐metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C−H bond. However, these high‐energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C−H functionalization reactions with diazoacetate derivatives, furnishing sp2–sp3 coupled products with moderate‐to‐good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition‐metal catalyst.

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Section: Methodsmentioning

confidence: 90%

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

2020

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“…Such a reaction would also be mechanistically distinct from recent work published by Gryko and co-workers that relies on the generation and alkylation of alpha-keto radicals from diazoacetate derivatives by using photoredox catalysis. [17] Herein, we report a method for C À H functionalization reactions of arene cation radicals with diazoacetate derivatives generated by organic photoredox catalysis. Computational and experimental studies support a unique mechanism involving cation-radical-meditated aromatic cyclopropana-tion followed by oxidative ring opening.…”

mentioning

confidence: 99%

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

2020

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Expanding the toolbox of C À H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition-metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic CÀH bond. However, these high-energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C À H functionalization reactions with diazoacetate derivatives, furnishing sp 2 -sp 3 coupled products with moderate-to-good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transitionmetal catalyst.Metallocarbenes are reactive organometallic species that may be generated by using a transition-metal precursor and diazoacetate derivatives. [1][2][3] The resulting carbene intermediate may then undergo CÀH insertion with reactive CÀH bonds (often aryl or alkyl), affording the corresponding alkylated adducts. However, owing to the high reactivity of metallocarbenes, aromatic substrates are often required to be present in excess for efficient reactivity.Among methodologies based on metallocarbene CÀH insertion that do not use a several-fold excess of arene, directing groups are often required. The groups of Fox [4] and Wang [5] have reported ortho-selective C À H functionalization of heterocycles by using diazoacetates. In addition, other directing groups, such as purines, [6] azacycles, [7] disubstituted anilines, [8] and phenols, [9] have been utilized in metallocarbene CÀH alkylation reactions. Collectively, these directing groups limit the synthetic applicability of metallocarbene C À H alkylation reactions.Recently, Suero and co-workers reported the synthesis of aryl diazoacetate derivatives under photoredox conditions. [10]

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“…In addition, diazo compounds are a kind of alternative reactive chemical reagent that are commonly used in C(sp 2 )-alkylation reactions. Gryko's group has described the photoalkylation of tryptophans with diazo esters in 67% yield (Scheme 17) [43]. It was worth noting that the catalyst loading could be as low as 0.2% when the reaction scale was 0.25 mmol, which is beneficial to scale up and apply in industry.…”

Section: C(sp 2 )-H Alkylationmentioning

confidence: 99%

Recent Advances in Rapid Synthesis of Non-proteinogenic Amino Acids from Proteinogenic Amino Acids Derivatives via Direct Photo-Mediated C–H Functionalization

Yuan

Liu

et al. 2020

Molecules

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Non-proteinogenic amino acids have attracted tremendous interest for their essential applications in the realm of biology and chemistry. Recently, rising C–H functionalization has been considered an alternative powerful method for the direct synthesis of non-proteinogenic amino acids. Meanwhile, photochemistry has become popular for its predominant advantages of mild conditions and conservation of energy. Therefore, C–H functionalization and photochemistry have been merged to synthesize diverse non-proteinogenic amino acids in a mild and environmentally friendly way. In this review, the recent developments in the photo-mediated C–H functionalization of proteinogenic amino acids derivatives for the rapid synthesis of versatile non-proteinogenic amino acids are presented. Moreover, postulated mechanisms are also described wherever needed.

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Photocatalytic Alkylation of Pyrroles and Indoles with α-Diazo Esters

Cited by 100 publications

References 36 publications

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

Recent Advances in Rapid Synthesis of Non-proteinogenic Amino Acids from Proteinogenic Amino Acids Derivatives via Direct Photo-Mediated C–H Functionalization

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