Pd(II)-Catalyzed Enantioselective Methylene C(sp3)–H Bond Activation
2016 · paper · Chemistry
Reports chiral acetyl-protected aminoethyl quinoline ligands that enable palladium-catalyzed enantioselective arylation of prochiral methylene C–H bonds on the same carbon in aliphatic amides. Six-membered ligand chelation to palladium is found essential for enantioselectivity.
1 finding
Reference or label Page 4: "we further optimized the reaction conditions for the arylation of 2a" names the product as the compound being arylated. In Figs. 2 and 3 the substrate is amide 1 and 2a is the arylated product; it should read "arylation of 1" (to give 2a).
- p. 4 Main text, paragraph beginning 'With the optimal ligand L35 in hand'
arylation of 2a and improved the enantioselectivity to 95:5 er
- p. 9 Fig. 3 reaction scheme and first entry
2a, 78% yield
- p. 4 Main text, same paragraph
The absolute configuration of the arylated product 2a
- p. 4 Fig. 3, 2i
95: 5 er
Judge's note: Page 4 image confirms the wording, and the same paragraph refers to "the arylated product 2a". The schemes in Fig. 2 and Fig. 3 (PDF pages 8 and 9) label the butyramide substrate 1 and the p-tolyl product 2a. The label-spacing points bundled into this cluster ("95: 5 er", "35%yield", "4h,72% yield", "85% yield,") are real and are recorded under C009.
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7 minor (typos and the like; most checked by the judge only)
Wording Page 2 attributes desymmetrization to "chiral mono-protected amino acid ligands (MPAA) ... (8, 9)", but reference 9 is titled "Palladium(II)-catalyzed enantioselective C(sp3)–H activation using a chiral hydroxamic acid ligand", a different ligand class from MPAA as the text defines it.
- p. 2 Main text, paragraph 2
different carbon centers (8, 9). Unfortunately, MPAA ligands have proven ineffective
- p. 5 Reference 9
enantioselective C(sp3)–H activation using a chiral hydroxamic acid ligand
- p. 2 Intro, paragraph 2
chiral mono-protected amino acid ligands (MPAA) has led to desymmetrization of methyl, cyclopropyl and cyclobutyl C–H bonds (Fig. 1A) at two different carbon centers (8, 9)
- p. 2 intro
chiral mono-protected amino acid ligands (MPAA)
Judge's note: Checked the sentence on the page 2 crop and reference 9 on the page 5 crop. The title of reference 9 names a hydroxamic acid ligand, so the sentence groups it loosely under MPAA; such ligands may be amino-acid derived, so this is imprecise wording, not a wrong reference. The repeated definition of MPAA and APAQ raised in the same cluster is a style point and is not confirmed.
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Wording Page 4: "Phenyl, ester, amino, ether and ketone functionalities at δ-and ε-positions ... (4k-p)": in Fig. 4 the ester of 4m (MeO2C–(CH2)4–) is attached one carbon further out, at the ζ-carbon. The phrase also lacks a space: "δ-and" should be "δ- and".
- p. 4 Main text, Fig. 4 discussion
ketone functionalities at δ-and ε-positions consistently afforded high enantioselectivity (4k-
- p. 10 Fig. 4, structure 4m (MeO2C–(CH2)4– chain)
4m, 68% yield
- p. 4 Scope paragraph on Fig. 4
δ-and ε-positions
Judge's note: Read the structures in a zoomed render of Fig. 4 (PDF page 10). With β = CH(Ar): 4k has Ph on the δ-carbon; 4l (CH2)3, 4n, 4o and 4p have the group on the ε-carbon; 4m is drawn with subscript 4, which puts the ester on ζ. This uses the same counting the text applies to 4e–j and 4q–s. One of six substrates falls outside the stated range, so this is a loose generalisation. The missing space is visible in the page 4 image.
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Wording Fig. 2 shows an "X-ray of L40b", and the caption ("The absolute configurations of L13, L21, L35 and L40b") and acknowledgments cite L40b, but the article draws and discusses only "anti-APAQ ligands (L40a, L41)"; L40b is never drawn or defined.
- p. 8 Fig. 2 caption
L13, L21, L35 and L40b were
- p. 8 Fig. 2, bottom panel
L40a, 13% yield, 31:69 er
- p. 4 Main text, anti-APAQ ligands
anti-APAQ ligands (L40a, L41)
- p. 5 Acknowledgments, CCDC list
L13, L21, L40b, L35, 2a,
Only the authors can say what is right here.
Judge's note: Zoomed render of the bottom panel of Fig. 2 (PDF page 8): the drawn anti ligands are L40a (13% yield, 31:69 er) and L41 (15% yield, 68:32 er), and the crystal picture is labelled L40b. Page 4 text names L40a and L41 only. The caption points to the supplementary material, which is not among the files, so L40b may be defined there (for example a salt or stereoisomer of L40a). Within the article the relationship between L40a and L40b is unstated. The supplement would settle what L40b is.
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Typo Abstract: "chiral acetyl-protected aminoethyl quinoline (APAQ) ligands that enables Pd(II)-catalyzed enantioselective arylation" has a plural subject with a singular verb; it should read "enable".
- p. 1 Abstract
(APAQ) ligands that enables
- p. 2 Main text, 'Herein we report' paragraph
(APAQ) that enable Pd(II)-catalyzed
- p. 1 Abstract
ligands that enables Pd(II)-catalyzed enantioselective arylation
- p. 2 Intro
The design of these new chiral ligands merge the key structural motifs
Judge's note: Read on the abstract crop. The parallel sentence on page 2 has "ligands (APAQ) that enable". The "design ... merge" quote attached to this cluster is handled in C002.
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Typo Page 2: "The design of these new chiral ligands merge the key structural motifs" has the singular subject "design" with a plural verb; it should read "merges".
- p. 2 Main text, 'Herein we report' paragraph
The design of these new chiral ligands merge the key structural motifs
Judge's note: Read on the page 2 crop. The head noun is "design"; the verb agrees with the adjacent "ligands" instead.
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Typo Page 4, Fig. 4 scope paragraph: "at the β-position (cyclopentyl, clyclohexyl)". "clyclohexyl" is misspelled and should read "cyclohexyl".
- p. 4 Main text, paragraph on Fig. 4 substrate scope
clyclohexyl) provided good enantioselectivity
- p. 4
at the β-position (cyclopentyl, clyclohexyl) provided good enantioselectivity
- p. 4 Main text, scope of amides
clyclohexyl
- p. 4 Scope paragraph on Fig. 4, line about 4e, 4f
(cyclopentyl, clyclohexyl)
Judge's note: In crop C005-a the printed text reads "(cyclopentyl, clyclohexyl) provided good enantioselectivity, but gave lower yields (4e, 4f)". The next sentence spells "cyclohexyl" correctly. The error is in the typeset page, so it is not an extraction artefact. This is a cosmetic misspelling.
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Typo Figure label formatting slips: Fig. 3 "2i, 58% yield 95: 5 er" (stray space in the ratio); Fig. 4 "4h,72% yield" (no space after the comma), "4p, 35%yield" (no space before "yield") and "4v*, 85% yield," (trailing comma).
- p. 4 Fig. 3, 2i label
95: 5 er
- p. 10 Fig. 4, 4h and 4v labels
4h,72% yield
Judge's note: All four are visible in the page images of Fig. 3 (PDF page 9) and Fig. 4 (PDF page 10, also checked in a zoomed render). The other labels use "N% yield" and "xx:yy er". Cosmetic; no number is affected. The Fig. 3 label is on PDF page 9, not page 4 as the cluster location says. The same points appear in C007's notes and are recorded here.
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