Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regioselective Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides
The Journal of Organic Chemistry, 2002 · paper · Chemistry
Reports a copper(I)-catalyzed reaction of terminal alkynes with azides on solid phase, giving 1,4-substituted [1,2,3]-triazoles in peptides. The authors report mild conditions, compatibility with peptide synthesis, and over 95% conversion and purity in most cases.
Checked: PDF from dg.dk, fetched 4 Oct 2026. Page numbers are those of that PDF.
8 findings
Substance The Results text (p.2) says "Compounds 9 and 10 were isolated in 79% and 87% yield", but Scheme 4 prints "9, yield: 73%" and the Experimental says "affording 8 mg of 9 (73% yield)".
- p. 2 Results, right column
10 were isolated in 79% and 87% yield
- p. 7 Experimental, compound 9
affording 8 mg of 9 (73% yield)
- p. 4 Scheme 4
9, yield: 73%
- p. 2 Results and Discussion, Compatibility paragraph
Compounds 9 and 10 were isolated in 79% and 87% yield
Only the authors can say what is right here.
Judge's note: I checked the p.2 text crop, the Scheme 4 image on p.4 and the Experimental on p.7. All three describe the same preparative run from resin 14, and nothing in the paper explains a second yield. The yield of 10 (87%) agrees in all three places. If the scale is 26 µmol (see C002), 8 mg of 9 (C18H21N5O6, about 403.4 g/mol) works out to about 76%, which matches neither printed value. Only the authors can say which figure is correct.
Second check: another model agreed
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Substance The text says "13 representative protected tripeptides acylated with propargylic acid", but Scheme 5 ("from 12 Protected Tripeptides"), Table 2 (12a-l) and the Experimental ("12 different Fmoc-amino acid-OPfp esters") all describe 12.
- p. 3 Compatibility paragraph
13 representative protected tripep-
- p. 7 Experimental 11a-l
acylated with 12 different Fmoc-amino acid-OPfp
- p. 5 Scheme 5 title
[1,2,3]-Triazole Formation from 12
- p. 5 Table 2 / Scheme 5
12 Protected Tripeptides
Judge's note: p.3 prints '13'. Scheme 5 and Table 2 on p.5 list 12 Xxx residues, a to l, and the Experimental on p.7 names 12 amino acids. No thirteenth tripeptide is described anywhere.
Second check: another model agreed · checked by hand
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Substance Table 1 assigns "8b 2-(2-deoxy)-Gal-SPh 78, 8c 4-C6H4NH2 90, 8d CH2CH(Ph)NH-Fmoc 79", whereas the Experimental assigns 8b = azide 19 (2-amino-3-phenylpropyl), 8c = the galactopyranoside and 8d = 4-aminophenyl.
- p. 3 Table 1, entries 8b-8d
8b 2-(2-deoxy)-Gal-SPh 78
- p. 7 Experimental 8b
R-N3: 19. HPLC: tR ) 11.8 min.
- p. 3 Table 1, rows 8b-8d
8b 2-(2-deoxy)-Gal-SPh 78 8c 4-C6H4NH2 90 8d CH2CH(Ph)NH-Fmocb 79
- p. 7 Experimental 8b, 8c, 8d
(8b). R-N3: 19.
Only the authors can say what is right here.
Judge's note: Table 1 on p.3 and the Experimental on p.7 disagree on which substituent belongs to each of 8b-8d. The Experimental also says Fmoc was removed before analysis, and its 8b formula (C36H44N9O6+) is that of the free amine, yet Table 1 lists 8d as NH-Fmoc. It is not clear which purity belongs to which compound, so only the authors can resolve this.
Second check: another model agreed
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Substance Resin 1 is described as "PEGA800 resin (2.5 g, 0.41 mmol/g, 10 mmol)", but 2.5 g at 0.41 mmol/g is about 1.0 mmol.
- p. 6 Experimental, resin 1
PE- GA800 resin (2.5 g, 0.41 mmol/g, 10 mmol)
Only the authors can say what is right here.
Judge's note: The p.6 image prints '10 mmol'. The paper's other scale statements fit 0.41 mmol/g (2.5 mg about 1 µmol; 5 mg about 2 µmol), so either the amount (probably 1.0 mmol) or the mass is wrong. This is a different defect from the mmol/µmol unit slip in C002.
Second check: another model agreed
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Reference or label The preparative scales are printed as "larger amount (26-42 mmol)", "14 (72 mg, 26 mmol, swollen in THF)" and "14 (118 mg, 42 mmol, swollen in THF)". The mass of resin and the milligram product yields fit µmol, not mmol.
- p. 2 Results
larger amount (26-42 mmol)
- p. 7 Experimental, compound 9
14 (72 mg, 26 mmol, swollen in THF)
- p. 7 Experimental, compound 10
14 (118 mg, 42 mmol
- p. 6 Experimental, resin 1
2.5 g, 0.41 mmol/g, 10 mmol
Judge's note: The page images print 'mmol'. Elsewhere the paper writes 'ca. 2 µmol' for 5 mg of resin and 'ca. 1 µmol' for 2.5 mg, using the µ sign, so this is not a lost micro sign in extraction. At about 0.4 mmol/g, 72 mg and 118 mg of resin carry roughly 30 and 48 µmol. The products (8 mg and 17 mg) also fit µmol amounts. The 1000-fold unit slip is the defect here; the separate 10 mmol figure for resin 1 is handled under C014.
Second check: another model agreed
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Reference or label Scheme 2, step vi, labels the resin that gives 6 as "2p, R = H", but the R = H resin is 2s (Experimental: "added to resin 2s"; Table 1: 3s = H).
- p. 2 Scheme 2, step vi
2p, R = H
- p. 6 Experimental, compound 6
were added to resin 2s
- p. 6 Experimental, Compound 6
added to resin 2s
Judge's note: The Scheme 2 image on p.2 shows '2p, R = H' above the arrow to 6. In Table 1, 3p is CH2CH(Ph)NH2 and 3s is H. The Experimental for compound 6 (p.6) uses resin 2s, and resin 2p is used for 4b. The scheme label is wrong.
Second check: another model agreed
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Reference or label The text says "Compounds 4a and 4b (Scheme 3) are examples where peptide synthesis has been continued", but 4a and 4b are drawn in Scheme 2.
- p. 4 Perspective, last line
Compounds 4a and 4b (Scheme
- p. 5 Perspective, first line
3) are examples where peptide synthesis has been
- p. 5 Perspective, start of column
3) are examples where peptide synthesis
Judge's note: The sentence runs from the foot of p.4 to the top of p.5. I checked both schemes: Scheme 3 on p.3 shows only 7 to 8a-e, while 4a and 4b appear in Scheme 2 on p.2.
Second check: another model agreed
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Reference or label The text says "Compounds 8a-d (Scheme 4) are also interesting as side chain analogues of N-substituted histidines", but 8a-e are in Scheme 3; Scheme 4 shows 9 and 10.
- p. 5 Perspective
Compounds 8a-d (Scheme 4) are also inter-
- p. 5 Perspective
Compounds 8a-d (Scheme 4)
Judge's note: p.5 prints 'Scheme 4'. Scheme 4 on p.4 is the synthesis of 9 and 10. Scheme 3 on p.3 is the preparation of the histidine analogues 8a-e.
Second check: another model agreed
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11 minor (typos and the like; most checked by the judge only)
Reference or label Reference "(28) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J. Tetrahedron Lett. 1991, 32, 923-926" appears in the reference list, but no citation marker 28 is found in the text.
- p. 8 Reference list
(28) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J.
Only the authors can say what is right here.
Judge's note: Searched the text layer and checked pages 5-8. Citations 26, 27 and 29 appear (29 at the data for compound 19), but 28 does not. It was probably intended for the azide preparation or Mitsunobu procedure. Only the authors can say where the marker belongs.
Second check: another model agreed
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Wording Scheme 2 labels the products "3a-s (74-95%)", but the text and Experimental say "purities ranging from 75% to 99%" / "75%-99% purity", and the lowest purity in Table 1 for 3b-3s is 75 (3m).
- p. 2 Scheme 2
3a-s (74-95%)
- p. 2 Results text
purities ranging from 75% to 99% (Table 1)
- p. 6 General procedure 3a-s
75%-99% purity (Table 1)
- p. 2 Results text
purities ranging from 75% to 99%
Only the authors can say what is right here.
Judge's note: The Scheme 2 image on p.2 shows '(74-95%)', and the scheme footnote says the (xx%) values are HPLC purities. In Table 1 on p.3 the 3-series values are >95, 91, 93, 83, 75, 90, 84, >95 and 84, so the minimum is 75. No entry is 74. The upper bounds also differ: the scheme says 95, the text says 99, and the table only prints >95. The authors should state which range is correct.
Second check: another model agreed
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Wording The text says '80-95% purity' for 12a–l, while the Experimental says 'purities ranging from 80% to 99%' and Table 2 lists seven entries at >95.
- p. 4 Compatibility paragraph
80-95% purity of the resulting peptido-
- p. 7 Experimental 12a-l
purities ranging from 80% to 99%, Table 2
- p. 4 Compatibility paragraph
above 95% and 80-95% purity of the resulting peptido-
- p. 4 Compatibility paragraph
all showed conversions above 95% and 80-95% purity
Judge's note: The two descriptions of the same data set differ in their upper bound. '95' may have been meant as shorthand for '>95'.
Second check: another model agreed
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Wording The Figure 3 caption prints "R = 0.0441 and Rw = 0.426". A weighted R about ten times the unweighted R is implausible for a solved structure.
- p. 5 Figure 3 caption
R = 0.0441 and Rw = 0.426
- p. 5 Figure 3 caption
R ) 0.0441 and Rw ) 0.426
Only the authors can say what is right here.
Judge's note: Rests on outside knowledge: in small-molecule refinement, wR is normally within a few times R, so 0.426 next to 0.0441 suggests a dropped digit (for example 0.0426). The crop confirms the printed values. The CIF in the Supporting Information is not among the files, so I cannot check the correct value.
Second check: another model agreed
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Wording The Conclusion says the reaction "was fully compatible with solid-phase peptide synthesis, all the amino acids, and their protecting groups", but only 12 Xxx residues (plus Phe/Gly) were tested, with some purities of 80-88%.
- p. 5 Conclusion
all the amino acids, and their protecting groups
- p. 5 Table 2
His(Trt) 80
Judge's note: Table 2 on p.5 covers Ala, Pro, Thr, Tyr, Asp, Asn, His, Cys, Met, Lys, Trp and Arg. Phe and Gly are in every peptide. Ser, Val, Leu, Ile, Glu and Gln were not tested. His(Trt), Cys(Trt), Met and Arg(Pmc) gave 80, 81, 85 and 88% purity. The word 'all' overstates the data.
Second check: another model agreed
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Wording Compound 17 is named "(1-Azidoethyl)carbamic Acid 9H-Fluoren-9-ylmethyl Ester, Fmoc-Gly-ψ[CH2N3] (17)". The paper's own label (Fmoc-Gly-ψ[CH2N3], from Fmoc-Gly-ol) and its 1H NMR data (two CH2 multiplets at 3.38 and 3.43 ppm) correspond to the 2-azidoethyl isomer.
- p. 8 Experimental 17 heading
(1-Azidoethyl)carbamic Acid 9H-Fluoren-9-ylmethyl
- p. 8 Compound 17 name
(1-Azidoethyl)carbamic Acid 9H-Fluoren-9-ylmethyl Ester, Fmoc-Gly-ψ[CH2N3] (17)
Judge's note: Viewed the heading on page 8. The ψ[CH2N3] descriptor, the starting material Fmoc-Gly-ol and the NMR assignments (CH2α, CH2N3, no CH3 doublet) all describe Fmoc-NH-CH2-CH2-N3. The locant 1 in the systematic name is therefore inconsistent with the paper's own data. The fix is evident (2-azidoethyl). The structure is clear from the label, so this is rated minor.
Second check: another model agreed
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Typo For 3e the Experimental prints "calcd (MH+ = C32H42N7O8+), 664.3 Da"; the dipropyl analogue of 3d (C31H38N7O8+, 636.3) is C33H42N7O8+, which gives 664.3.
- p. 6 Experimental 3e
C32H42N7O8+), 664.3 Da
Judge's note: The crop on p.6 shows C32. 3d (diethyl) is C31H38N7O8+, and 3e (dipropyl) adds C2H4, giving C33H42N7O8+. Its monoisotopic mass is about 664.31, which matches the printed mass; C32H42N7O8+ would be about 652.3. The formula is a typo and the mass is correct.
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Typo The compound name reads 'carbonyl-Phe-Gly-Phe Gly-OH (3a)', with a hyphen missing between Phe and Gly.
- p. 6 Compound 3a name
carbonyl-Phe-Gly-Phe Gly-OH (3a)
Judge's note: The crop shows the space mid-line, so this is not a line-break artefact.
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Typo The 13b entry reads 'calcd (M = C34H39N8O6+)', while the ion is MH+ (as for 13a and the adjacent 'found (MH+)').
- p. 7 Experimental 13b
calcd (M ) C34H39N8O6+), 655.3 Da
- p. 7 Compounds 13a and 13b, 13b entry
calcd (M )
Judge's note: The page image shows '(M ='.
Second check: none (judge only)
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Typo The 13C observation frequency is given as "62.5 MHz, CDCl3" for compounds 15-18 but as "62.9 MHz" for compounds 9, 10 and 19. The Experimental section names a single Bruker DRX250 (250 MHz) for all 1H and 13C spectra.
- p. 8 Compounds 15-18 13C NMR
13C NMR (62.5 MHz, CDCl3)
- p. 7 Compounds 9/10 13C NMR
13C NMR (62.9 MHz, DMSO-d6)
Judge's note: Viewed the crops on pages 7 and 8. Both values are printed for the same stated instrument. 62.5 MHz is likely a nominal rounding rather than a different spectrometer. This is a minor consistency point only.
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Typo The HR-MS entry for 17 (Fmoc-Gly-ψ[CH2N3]) prints "calcd (M + Na+ = C27H31N5O6Na+), 331.1165 Da"; the mass fits C17H16N4O2Na+, not the printed formula.
- p. 8 Experimental 17
C27H31N5O6Na+), 331.1165 Da
- p. 8 Compound 17 HR-MS
calcd (M + Na+ ) C27H31N5O6Na+), 331.1165 Da
Judge's note: The p.8 crop confirms the printed formula. Compound 17, Fmoc-NHCH2CH2N3, is C17H16N4O2. Its M+Na+ is about 331.117, which matches the calculated and found values (331.1165 and 331.1170). C27H31N5O6Na works out to about 544. The formula is a typo and the mass is correct.
Second check: none (judge only)