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Synlett 2013; 24(10): 1286-1290
DOI: 10.1055/s-0033-1338452
DOI: 10.1055/s-0033-1338452
letter
Direct Domino Synthesis of Azido-Dienoic Acids: Potential Linker Units
Further Information
Publication History
Received: 13 February 2013
Accepted after revision: 05 April 2013
Publication Date:
08 May 2013 (online)
![](https://www.thieme-connect.de/media/synlett/201310/lookinside/thumbnails/10.1055-s-0033-1338452-1.jpg)
Abstract
We report an atom-economical domino synthesis of functionalized and stereodefined dienes. This method hinges on an allylic alkylation–electrocyclic ring-opening sequence and allows direct access to doubly vinylogous azido-dienoic acids bearing challenging substitution patterns. This class of compounds represents useful linkers in chemical biology by virtue of the orthogonality between the azido and carboxylic acid moieties.
Supporting Information
- for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
- Supporting Information
-
References and Notes
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13 Even if azido nucleophiles generally lead to products of global retention in palladium-mediated allylic alkylation, exceptions are well documented in the literature (especially when a monodentate ligand is used). See, for example: Murahashi SI, Taniguchi Y, Imada Y, Tanigawa Y. J. Org. Chem. 1989; 54: 3292
- 14 The reaction can be performed in up to 3.0 mmol scale affording 350 mg of the desired dienoic acid 4a.
- 15 General Procedure for the Synthesis of Azidodiene 4 In a Schlenk flask, Pd(PPh3)4 (9.0 mg, 8 μmol, 5 mol%) was evacuated/backfilled with argon three times and dissolved in THF (3.1 mL). TMSN3 (36 μL, 0.312 mmol, 2.0 equiv) was added to the stirred solution of Pd(PPh3)4, and the mixture was cooled to 0 °C. After 5 min, an Et2O solution of lactone 1 (0.20 M in Et2O, 0.78 mL, 0.156 mmol, 1.0 equiv) was added dropwise to the mixture, and the mixture was then stirred at 0 °C for 2 days. The solution was quenched with H2O, and Et2O was added to the mixture. The organic phase was extracted three times with sat. NaHCO3. The aqueous phases were acidified using 1 M HCl, extracted three times with EtOAc, and the combined extracts were evaporated to give the azido diene. (2E,4E)-5-Azidopenta-2,4-dienoic Acid (4a) Compound 4a was obtained as a yellow powder in 81% yield according to the general procedure. 1H NMR (300 MHz, CD3COCD3): δ = 7.30 (dd, J = 15.4, 11.4 Hz, 1 H), 7.01 (d, J = 13.2 Hz, 1 H), 6.18 (dd, J = 13.2, 11.4 Hz, 1 H), 5.90 (d, J = 15.4 Hz, 1 H). 13C NMR (75 MHz, CD3COCD3): δ = 167.8, 142.6, 138.8, 120.7, 118.2. FTIR (neat): νmax = 2926, 2567, 2283, 2103, 1673, 1619, 989 cm–1. ESI-HRMS: m/z calcd for C5H5N3O2 [M]+: 139.0380; found: 139.0382.
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- 20 It should be noted, however, that these rules, while applicable to the series at hand, should not be used indiscriminately without consideration for possible steric and electronic effects of additional substitutions. See Supporting Information for tabular data on coupling constants and chemical shifts
- 21 For further details, see Supporting Information.
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- 23 General Procedure for the Click Reaction According to Conditions B To a mixture of azido diene 4a (15 mg, 0.11 mmol, 1.0 equiv) in THF (0.5 mL) was added the corresponding acetylene (0.21 mmol, 2.0 equiv) followed by H2O (0.25 mL). The reaction mixture was stirred at r.t. for 12 h. EtOAc was added to the mixture, and the resulting solution was washed with three times with 1 M HCl. The organic phase was dried over MgSO4, filtered, and the solvent was removed under vacuum to afford the desired triazole 5d. (2E,4E)-5-(4,5,6,7,8,9-Hexahydro-1H-cycloocta[d][1,2,3]triazol-1-yl)penta-2,4-dienoic Acid (5d) Compound 5d was obtained in quantitative yield. 1H NMR (500 MHz, CD3COCD3): δ = 7.71 (d, J = 13.6 Hz, 1 H), 7.50 (dd, J = 15.4, 11.9 Hz, 1 H), 7.26 (dd, J = 13.6, 11.9 Hz, 1 H), 6.20 (d, J = 15.4 Hz, 1 H), 2.96 (t, J = 6.7 Hz, 2 H), 2.88 (t, J = 6.7 Hz, 2 H), 1.89–0.86 (m, 8 H). 13C NMR (125 MHz, CD3COCD3): δ = 167.7, 145.7, 142.4, 134.5, 130.4, 124.2, 119.4, 29.5, 26.9, 26.8, 25.4, 25.1, 21.7. FTIR (neat): νmax = 2922, 2859, 1683, 1619, 1049, 995 cm–1. ESI-HRMS: m/z calcd for C13H16N3O2 [M – H]–: 246.1259; found: 246.1248.
- 24 General Procedure for the Click Reaction According to Conditions A To a mixture of azido diene 4a (15 mg, 0.11 mmol, 1.0 equiv) and the corresponding acetylene (0.21 mmol, 2.0 equiv) in THF (0.5 mL) was added a solution of CuSO4·5H2O (5.4 mg, 0.02 mmol, 0.2 equiv) in H2O (0.25 mL) followed by a solution of sodium ascorbate (13 mg, 0.06 mmol, 0.6 equiv) in H2O (0.25 mL). The reaction mixture was stirred at r.t. for 12 h. EtOAc was added to the mixture, and the resulting solution was washed three times with 1 M HCl. The organic phase was dried over MgSO4, filtered, and the solvent was removed under vacuum to afford the desired triazole 5.
- 25 Procedure for the Click Reaction in Buffer Solution To a mixture of azido diene 4a (15 mg, 0.11 mmol, 1.0 equiv) and the corresponding acetylene (0.21 mmol, 2.0 equiv) in t-BuOH (0.5 mL) was added a solution of CuSO4·5H2O (5.4 mg, 0.02 mmol, 0.2 equiv) in H2O (0.25 mL), followed by a solution of sodium ascorbate (13 mg, 0.06 mmol, 0.6 equiv) in H2O (0.25 mL). Finally, a 0.5 mL solution of 0.1 M Tris·HCl in H2O was added. The reaction mixture was stirred at r.t. for 12 h. EtOAc was added to the mixture, and the resulting solution was washed three times with 1 M HCl. The organic phase was dried over MgSO4, filtered, and the solvent was removed under vacuum to afford the desired triazole 5a. (2E,4E)-5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)penta-2,4-dienoic Acid (5a) Compound 5a was obtained as a yellow paste in 85% yield according to conditions C. 1H NMR (500 MHz, CD3COCD3): δ = 8.35 (s, 1 H), 7.94 (d, J = 14.2 Hz, 1 H), 7.50 (dd, J = 15.1, 11.4 Hz, 1 H), 7.21 (dd, J = 14.2, 11.4 Hz, 1 H), 6.17 (d, J = 15.1 Hz, 1 H), 4.55 (s, 2 H), 3.35 (s, 3 H). 13C NMR (125 MHz, CD3COCD3): δ = 167.3, 146.5, 141.8, 132.4, 128.8, 122.1, 119.2, 66.0, 58.1. FTIR (neat): νmax = 3094, 2931, 2887, 1677, 1644, 1619, 1044, 993 cm–1. ESI-HRMS: m/z calcd for C9H10N3O3 [M – H]–: 208.0726; found: 208.0728.
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- 28 General Procedure for the Coupling of N-Nucleophiles (Conditions A) To a solution of azido diene 4a (15 mg, 0.11 mmol, 1.0 equiv) and amine 10.12 mmol, 1.1 equiv) in CH2Cl2 (2 mL) were added HOBt (16 mg, 0.12 mmol, 1.1 equiv) and EDCI (23 mg, 0.12 mmol, 1.1 equiv) at 0 °C. The resulting mixture was allowed to warm to r.t. and stirred for 12 h. H2O (5 mL) and CH2Cl2 (5 mL) were added, and the organic layer was washed with sat. NaHCO3, brine, and dried over MgSO4. After filtering, the solvent was removed under vacuum, and the product was purified by column chromatography on silica gel (pentane–EtOAc, 95:5) to afford the desired amides 6. (S)-tert-Butyl 2-[(2E,4E)-5-Azidopenta-2,4-dienamido]-3-(4-hydroxyphenyl)propanoate (6a) Compound 6a was obtained as a pale yellow oil in 55% yield. 1H NMR (500 MHz, CD3COCD3): δ = 8.23 (s, 1 H), 7.28 (br d, J = 8.5 Hz, 1 H), 7.15 (app t, J = 12.7 Hz, 1 H), 7.05 (d, J = 7.5 Hz, 2 H), 6.87 (d, J = 12.7 Hz, 1 H), 6.74 (d, J = 7.5 Hz, 2 H), 6.11 (d, J = 14.8 Hz, 1 H), 6.05 (app t, J = 12.7 Hz, 1 H), 4.62 (m, 1 H), 2.98 (dd, J = 13.9, 6.1 Hz, 1 H), 2.91 (d, J = 13.9, 8.1 Hz, 1 H), 1.39 (s, 9 H). 13C NMR (125 MHz, CD3COCD3): δ = 171.7, 165.8, 157.1, 137.8, 136.9, 131.3 (2 C), 128.7, 124.1, 118.6, 115.9 (2 C), 81.6, 55.4, 37.8, 28.1 (3 C). FTIR (neat): νmax = 3303, 2978, 2939, 2106, 1719, 1513, 1147 cm–1. ESI-HRMS: m/z calcd for C18H22N4O4Na [M + Na+]: 381.1534; found: 381.1533. General Procedure for the Coupling of O-Nucleophiles To a stirred solution of azido diene 4a (0.07 mmol, 1.0 equiv) in CH2Cl2 (1 mL) were added DMF (1 drop) followed by oxalyl chloride (0.01 mmol, 1.5 equiv) at 0 °C. After 30 min, the solution was added to a mixture of alcohol (0.09 mmol, 1.1 equiv) and NaH (60% in mineral oil, 0.09 mmol, 1.1 equiv) in CH2Cl2 (1 mL). The resulting mixture was stirred for 12 h at r.t. H2O (5 mL) and CH2Cl2 (5 mL) were added to the reaction mixture, and the layers were separated. The organic phase was washed three times with H2O, brine, and dried over MgSO4. The solvent was removed under vacuum, and the product was purified by column chromatography on silica gel (pentane–EtOAc, 6:4) to afford the desired ester 6. (2E,4E)-(3S,10S,13R,14S,17R)-14-Hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 5-Azidopenta-2,4-dienoate (6c) Compound 6c was obtained as a colorless solid in 22% yield. 1H NMR (500 MHz, CD3COCD3): δ = 7.29 (m, 1 H), 7.01 (t, J = 11.3 Hz, 1 H), 6.17 (t, J = 11.8 Hz, 1 H), 5.93–5.87 (m, 2 H), 5.01 (d, J = 18.5 Hz, 1 H), 4.85 (d, J = 18.5 Hz, 1 H), 3.28 (s, 1 H), 2.27–2.11 (m, 2 H), 2.09–2.08 (m, 3 H), 1.96–1.20 (m, 18 H), 0.98 (s, 3 H), 0.91 (s, 3 H). 13C NMR (125 MHz, CD3COCD3): δ = 176.3, 174.6, 160.8, 124.4, 123.9, 117.8, 115.6, 110.5, 85.5, 74.1, 70.7, 51.8, 50.6, 42.5, 40.4, 40.3, 36.2, 36.0, 33.6, 31.4, 31.4, 27.6, 27.4, 25.8, 24.1, 22.1, 22.0, 16.2. FTIR (neat): νmax = 2929, 2101, 1746, 1701, 1602, 1165, 989 cm–1. ESI-HRMS: m/z calcd for C28H38N3O5 [M + H]+: 496.2806; found: 496.2809.
For a drug containing the azido group, see
For vinyl azide syntheses, see:
For examples of dienyl azide synthesis, see:
For spontaneous ring-opening of push–pull cyclobutenes, see:
For spontaneous ring-opening of cyclobutenes, see:
For examples of allylic alkylation with azides, see:
For overviews of ‘click’ chemistry, see:
For hapten applications, see: