Decarboxylative sp3 C–N Coupling via Dual Copper and Photoredox Catalysis
Nature, 2018 · paper · Chemistry
Combines copper and photoredox catalysis to couple alkyl carboxylic acids with nitrogen nucleophiles, forming sp3 C–N bonds at room temperature in minutes to an hour. It works with primary, secondary and tertiary acids and applies to complex drug molecules.
2 findings
Substance Text gives the primary-acid range as "(13–21, 50–82% yield)" but Figure 3 prints "14, 84% yield", so the upper bound of the range for 13–21 should be 84%.
- p. 3 Main text, paragraph on carboxylic acid scope
(13–21, 50–82% yield)
- p. 15 Figure 3, primary alkyl acids
14, 84% yield
Judge's note: Read page 3 text and the Figure 3 image on page 15. Figure yields for 13–21 are 65, 84, 54, 63, 64, 80, 50, 82, 80, so the minimum is 50 and the maximum is 84 (compound 14, n-pentyl). The caption's non-photonic yield for 14 is 70%, so 84% is the isolated standard-condition yield. No statement excludes 14 from the range. The other ranges in the text (22–24, 26–31, 32–36) match the figure exactly.
Second check: another model agreed
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Substance Text says "regioselective N-alkylation of the indazole was observed in 80% yield" and then separately describes the 7.4 mmol run, whereas Figure 5a prints "88% yield" for 64→65 and "80% yield (gram-scale)".
- p. 5 Main text, sequential coupling paragraph
regioselective N-alkylation of the indazole was observed in 80% yield
- p. 17 Figure 5a, under compound 65
88% yield
- p. 17 Figure 5a, under compound 65
80% yield (gram-scale)
- p. 5 Results text, sequential coupling paragraph
regioselective N-alkylation of the indazole was observed in 80% yield. Moreover, we have executed the regioselective N-alkylation step on a 7.4 mmol scale to prepare 1.45 g
Only the authors can say what is right here.
Judge's note: Read page 5 text and the Figure 5a image on page 17. The figure gives two yields for 65: 88% and 80% (gram-scale). My check: 65 is C14H17N3O, MW about 243.3, so 7.4 mmol is 1.80 g theoretical and 1.45 g is about 80.5%. The 80% therefore belongs to the gram-scale run. The text quotes 80% as the observed yield before introducing the scale-up with "Moreover", and never mentions 88%. The authors may have meant to quote only the gram-scale figure, so this is a query rather than a correction.
Second check: another model agreed
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12 minor (typos and the like; most checked by the judge only)
Wording Figure 2 caption: "In all cases, the presence of both the copper(I) catalyst and the photoredox catalyst under light irradiation conditions is crucial to achieve the best efficiency", yet indazole 11c gives 86% with Cu(I) and no light versus 90% under full conditions.
- p. 14 Figure 2 caption b
In all cases, the presence of both the copper(I) catalyst and the photoredox catalyst under light irradiation conditions is crucial
- p. 3 main text
the alkylation of indazole 11c is successful with or without photocatalysis (90% versus 86% yield)
Judge's note: Read the Figure 2b table on the page 14 image. For 11c the yields are 86% (Cu, no light), 86% (Cu, light) and 90% (with photocatalyst). The page 3 text itself says the indazole alkylation "is successful with or without photocatalysis (90% versus 86% yield)". The caption is literally true, since the highest yield in each column is under full conditions, but "crucial" "in all cases" overstates a 4-point difference for 11c. This is a wording point only.
Second check: another model agreed
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Wording Figure 4 title "Decarboxylative C–N couplings of cyclohexyl carboxylic acid with a variety of N-nucleophiles" does not cover the pharmaceutical products 58 (n-pentyl bicyclopentyl), 59, 60 and 63 (N-cyclobutyl), which come from other acids.
- p. 16 Figure 4 caption title
Decarboxylative C–N couplings of cyclohexyl carboxylic acid with a variety of N-nucleophiles
- p. 5 Main text, pharmaceuticals paragraph
Using three separate carboxylic acids
Judge's note: Read the Figure 4 image on page 16. Products 37–57, 61 and 62 are N-cyclohexyl. Product 58 carries an n-pentyl bicyclo group, and 59, 60 and 63 carry cyclobutyl. The page 5 text confirms "Using three separate carboxylic acids" for 58–63. The title describes most of the figure but not all of it. This is a labelling imprecision, not a data error.
Second check: another model agreed
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Typo Missing article: "coupling takes place at least hindered site of these heteroaromatic nucleophiles" should read "at the least hindered site".
- p. 4 Main text, N-nucleophile scope paragraph
coupling takes place at least hindered site of these heteroaromatic nucleophiles
- p. 4 N-nucleophile scope paragraph, regioselectivity sentence
takes place at least hindered site of these heteroaromatic nucleophiles
- p. 4 regioselectivity paragraph
takes place at least hindered site
Judge's note: Seen on the page 4 image as quoted. The same sentence also has a stray comma after "ligated copper complex". Not an extraction artefact.
Second check: none (judge only)
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Typo Missing comma in "(41 58% yield)"; should read "(41, 58% yield)".
- p. 4 Main text, N-heterocycle list
(41 58% yield)
Judge's note: Seen on the page 4 image: "indoles (41 58% yield)" has no comma, whereas every other entry in the list uses the form "(51, 75% yield)".
Second check: none (judge only)
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Typo Misspelling: "the relative acidity of the two N–H moities in substrate 64" should read "moieties".
- p. 5 Main text, last paragraph
the two N–H moities in
- p. 17 Figure 5 title
nucleophillic substitutions
- p. 17 Figure 5 caption
r.r., regiomeric ratio
- p. 5 text
N–H moities
Judge's note: Seen on the page 5 image. This cluster also bundles "nucleophillic", "regiomeric" and "at least hindered site"; those are judged under C013, C014 and C002. This verdict covers only "moities".
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Typo Missing word: "we performed a series experiments to compare" should read "a series of experiments".
- p. 6 Main text, final paragraph before Methods
a series experiments to compare
- p. 6 Final results paragraph (comparison with nucleophilic substitution)
we performed a series experiments to compare
- p. 6 last paragraph of main text
we performed a series experiments
- p. 6
we performed a series experiments to compare the decarboxylative protocol
Judge's note: Seen on the page 6 image, across the line break "we performed / a series experiments". Not an extraction artefact.
Second check: none (judge only)
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Typo Reference 2 title is printed as "Selected Copper-Based Reaction for C–N, C–O, C–S, and C–C Bond Formation"; the plural "Reactions" is expected.
- p. 10 Reference 2
Selected Copper-Based Reaction for C–N, C–O,
Only the authors can say what is right here.
Judge's note: Rests on outside knowledge: the published title of the cited Angew. Chem. review (Bhunia et al., 2017) is believed to use "Reactions". The page 10 image shows the singular "Reaction" as quoted, which reads oddly after "Selected". The true title cannot be checked from the files.
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Typo Reference 24 title is printed as "A new general method of hemolytic alkylation of protonated heteroaromatic bases"; "hemolytic" should presumably be "homolytic".
- p. 11 Reference 24
A new general method of hemolytic alkylation of
- p. 11 Reference 24
A new general method of hemolytic alkylation
- p. 11 Ref 26
Secretase Inhibtor
- p. 11 Ref 24
hemolytic alkylation
Only the authors can say what is right here.
Judge's note: Rests on outside knowledge: the Minisci 1989 Tetrahedron Lett. title is believed to read "homolytic alkylation". The page 11 image shows "hemolytic" as quoted. "Hemolytic" (blood-cell lysis) makes no sense for a radical alkylation of heteroaromatic bases, so this is very likely an autocorrect error. The "Inhibtor" item bundled into this cluster is judged under C009.
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Typo Reference 26: misspelling "γ-Secretase Inhibtor" should read "Inhibitor".
- p. 11 Reference 26
γ-Secretase Inhibtor
- p. 11
Potent and Orally Active γ-Secretase Inhibtor
Judge's note: Seen on the page 11 image as quoted. A plain misspelling that needs no outside fact.
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Typo Reference 30 title is printed as "A General Small-Scale Reactor To Enable Standardization and Acceleration to Photocatalytic Reactions"; "Acceleration of" is expected.
- p. 12 Reference 30
Standardization and Acceleration to Photocatalytic
Only the authors can say what is right here.
Judge's note: Rests on outside knowledge: the published ACS Cent. Sci. title is believed to read "Acceleration of Photocatalytic Reactions". The page 12 image shows "Acceleration to" as quoted, which is ungrammatical. The true title cannot be checked from the files.
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Typo Figure 5 title: misspelling "comparisons with nucleophillic substitutions" should read "nucleophilic".
- p. 17 Figure 5 caption title
comparisons with nucleophillic substitutions
- p. 17 Figure 5 title
nucleophillic substitutions
Judge's note: Seen on the page 17 image in the bold caption title. The panel b heading and the caption body both spell "nucleophilic" correctly.
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Typo Figure 5 caption defines "r.r., regiomeric ratio"; the standard term is "regioisomeric ratio".
- p. 17 Figure 5 legend abbreviations
r.r., regiomeric ratio
Judge's note: Seen on the page 17 image as quoted. The paper uses "regioisomer" and "regioisomeric" elsewhere (pages 3–4), so "regiomeric" is inconsistent and probably a slip. The form does appear occasionally in the literature, so this is filed as an observation.
Second check: none (judge only)