Enantioselective α-Trifluoromethylation of Aldehydes via Photoredox Organocatalysis
Journal of the American Chemical Society, 2009 · paper · Chemistry
Describes asymmetric α-trifluoromethylation of aldehydes by merging enamine organocatalysis with iridium photoredox catalysis, using trifluoromethyl iodide as the CF3 source. The approach targets a previously elusive enantioselective transformation.
2 findings
Substance Text: "can be accommodated without loss in enantiocontrol (entries 5–7, 10, and 11, ≥96% ee)", but Table 2 entry 7 reads "73% yield 90% ee".
- p. 2 Results text, aldehyde scope paragraph
(entries 5–7, 10, and 11, ≥96% ee)
- p. 9 Table 2, entry 7
73% yieldd 90% ee
- p. 2 Results text, aldehyde scope
entries 5–7, 10, and 11, ≥96% ee
Only the authors can say what is right here.
Judge's note: Table 2 (page 9, upright image) gives ee for entries 5, 6, 7, 10, 11 as 99, 98, 90, 99, 99. Entry 7 (adamantyl, catalyst 11 per footnote d and ref 20) is 90% ee, below the stated floor of 96% and the lowest value in the table. Footnote d only says another catalyst was used and does not explain the gap. Either the bound in the text or the table value is wrong; only the authors can say which.
Second check: another model agreed
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Substance Text: "(entries 1–3 and 5–8, 66–88% yield, 96–99% ee)", but Table 3 yields for those entries are 73, 69, 67, 85, 71, 68 and 89%, i.e. 67–89%.
- p. 3 First paragraph, Table 3 discussion
entries 1–3 and 5–8, 66–88% yield, 96–99%
- p. 11 Table 3, entries 3 and 8
67% yield 96% ee
- p. 11 Table 3, entry 8
89% yieldd 99% ee
- p. 3 Results, perfluoroalkyl scope paragraph
(entries 1–3 and 5–8, 66–88% yield, 96–99%
Judge's note: Table 3 (page 11, upright image): entry 1 73%, 2 69%, 3 67%, 5 85%, 6 71%, 7 68%, 8 89%. Minimum 67 and maximum 89; neither 66 nor 88 appears anywhere in the table (entry 4 is 72%). Both ends of the quoted range are off by one. The ee range 96–99% matches. No footnote or text gives other yields.
Second check: another model agreed
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10 minor (typos and the like; most checked by the judge only)
Wording Introduction: "the enantioselective α-alkylfluorination of carbonyl derived enolates (or enolate equivalents) remains an elusive goal" uses a term that does not describe the reaction under discussion (α-trifluoromethylation / α-fluoroalkylation, as in refs 6-7 and the next sentence).
- p. 1 Introduction
α-alkylfluorination of carbonyl derived enolates
Judge's note: Page 1 image reads "α-alkylfluorination". The term appears nowhere else; the paper otherwise says α-trifluoromethylation, α-perfluoroalkylation or fluoroalkylation, and refs 6 and 7 (page 4) concern trifluoromethylation of enolates and enamines. Probably a transposition of "fluoroalkylation", but it could be a loose coinage, so it is kept as an observation.
Second check: another model agreed
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Wording Text: "can be employed in a reductive amination sequence without significant loss in enantioselectivity to produce β-trifluoromethyl amines", but Scheme 2 shows the aldehyde at 97% ee and the β-CF3 amine at 87% ee.
- p. 3 Second paragraph, Scheme 2 discussion
without significant loss in
- p. 7 Scheme 2, β-CF3 amine
87% ee
- p. 3 Paragraph on product derivatisation (Scheme 2)
reductive amination sequence without significant loss in
- p. 9 Scheme 2, starting aldehyde
97% ee
Only the authors can say what is right here.
Judge's note: Scheme 2 (page 7 image): aldehyde 97% ee; β-CF3 alcohol 97% ee; α-CF3 acid 96% ee; β-CF3 amine 95% yield, 87% ee; α-CF3 amine 92% ee. The reductive amination shows the largest drop in the scheme (10 points), more than the Curtius product, for which the text says careful conditions are essential. "Significant" is a judgement word, and the 87% could itself be a misprint, so this is a query for the authors.
Second check: another model agreed
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Wording Text: "n-perfluoroalkyl substrates of varying chain length undergo reductive radical formation and enamine addition ... (entries 1–3 and 5–8 ...)", but in Table 3 only entries 1–3 are n-perfluoroalkyl chains; entries 5–8 are CF2C6F5, CF2OCF3, CF2Br and CF2CO2Et.
- p. 3 First paragraph, Table 3 discussion
n-perfluoroalkyl substrates
- p. 11 Table 3, entries 5–8 (product structures)
85% yield 98% ee
- p. 3 Results, perfluoroalkyl scope paragraph
n-perfluoroalkyl substrates of varying chain length undergo reductive radical formation and enamine addition without loss in enantiocontrol or reaction efficiency (entries 1–3 and 5–8
- p. 3 Paragraph introducing Table 3
n-perfluoroalkyl substrates of varying chain length
Only the authors can say what is right here.
Judge's note: Table 3 (page 11, upright image): entries 1–3 carry CF2CF3, (CF2)2CF3, (CF2)3CF3; entries 5–8 carry CF2C6F5, CF2OCF3, CF2Br, CF2CO2Et. These are the benzylic, ether and ester difluoromethylene cases that the following sentence mentions without entry numbers. The entry pointer covers substrates the sentence does not describe. The authors may have meant the parenthesis as a summary of the whole table except entry 4, so it is rated as a wording or pointer query.
Second check: another model agreed
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Typo Supporting Information note: "Experimental procedures, and spectral data are provided (PDF)." has a comma before "and" in a two-item list.
- p. 1 Supporting Information note
Experimental procedures, and spectral data are provided (PDF).
Judge's note: Page 1 image shows the comma as quoted. Trivial punctuation; possibly left over from a longer list.
Second check: none (judge only)
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Typo Garbled wording: "reduction or oxidation of the formyl group is possible to generate β-hydroxy and as α-trifluoromethyl acids" (stray "as"; "β-hydroxy" has no noun).
- p. 3 Second paragraph, Scheme 2 discussion
β-hydroxy and as α-
- p. 3 Paragraph on Scheme 2, second sentence
is possible to generate β-hydroxy and as α-
- p. 3 Scheme 2 discussion
generate β-hydroxy and as α-trifluoromethyl acids
- p. 3 paragraph before the summary
generate β-hydroxy and as α-
Judge's note: Page 3 image reads exactly as quoted. Scheme 2 (page 7) shows the reduction product as a β-CF3 alcohol and the oxidation product as an α-CF3 acid, so the intended text is along the lines of "β-trifluoromethyl alcohols as well as α-trifluoromethyl acids".
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Typo "Moreover, benzylic, -ester, and α-ether difluoromethylene carbons" has a bare "-ester" with a leading hyphen and no prefix (presumably "α-ester").
- p. 3 First paragraph
benzylic, -ester, and α-ether
- p. 3 Results, perfluoroalkyl scope paragraph, last sentence
benzylic, -ester, and α-ether difluoromethylene
Judge's note: Page 3 image shows "-ester" with no Greek letter before the hyphen, so this is not a text-layer loss. By parallel with "α-ether" and Table 3 entry 8 (CF2CO2Et), a dropped α is the likely cause.
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Typo Acknowledgments: "the Natural Sciences and Research Council (NSERC) of Canada" omits the word "Engineering".
- p. 3 Acknowledgments
Natural Sciences and Research Council (NSERC)
- p. 3 Acknowledgments
Natural Sciences and Research Council (NSERC) of Canada
Only the authors can say what is right here.
Judge's note: Rests on outside knowledge: NSERC is the Natural Sciences and Engineering Research Council of Canada. Page 3 image reads as quoted. The printed abbreviation NSERC contains an E that the spelled-out name does not account for, which supports the finding from the page itself.
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Typo Acknowledgments: "Financial support was provided by the NIHGMS (R01 GM078201-01-01)" uses "NIHGMS" where the usual abbreviation is NIGMS.
- p. 3 Acknowledgments
NIHGMS (R01 GM078201-01-01)
Only the authors can say what is right here.
Judge's note: Rests on outside knowledge: the National Institute of General Medical Sciences is abbreviated NIGMS (or NIH-NIGMS). Page 3 image reads "NIHGMS". It may be a deliberate blend of NIH and GMS; the meaning is unaffected.
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Typo Reference 12 labels its second citation "(b) Flamigni L, Barbieri A ..." but the first citation (Slinker JD et al.) has no "(a)" label.
- p. 4 Reference 12
see: (b) Flamigni L, Barbieri A
- p. 4 Reference 12
see: (b) Flamigni L
Judge's note: Page 4 image: reference 12 reads "... see: Slinker JD, Gorodetsky AA ... For a review on the photo-properties of iridium complexes, see: (b) Flamigni L ...". There is no "(a)" before Slinker. Cosmetic.
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Typo Note "22. General Procedure for the Enantioselective α–Trifluoromethylation of Aldehydes." has no callout in the text, tables or schemes.
- p. 4 Reference 22
22. General Procedure for the Enantioselective α–Trifluoromethylation of Aldehydes.
Judge's note: Callouts in the body text on pages 1-3 are 1-19 and 21. Ref 20 is called from Table 2 footnote d on page 10. No superscript 22 appears in the text layer of any page, nor on the page images of Table 2, Table 3 and Scheme 2. Table 1 and Scheme 1 were checked in the text layer only. The callout may have been lost when the author manuscript was reformatted; harmless to the reader.
Second check: none (judge only)