A Tandem [3+2] Cycloaddition–Elimination Cascade Reaction to Generate Pyrrolo-[3,4-c]pyrrole-1,3-diones

Guillermo Martinez-Ariza; Justin Dietrich; Fabio De Moliner; Christopher Hulme

doi:10.1055/s-0033-1338872

Synlett, Inhaltsverzeichnis

Synlett 2013; 24(14): 1801-1804
DOI: 10.1055/s-0033-1338872

letter

A Tandem [3+2] Cycloaddition–Elimination Cascade Reaction to Generate Pyrrolo-[3,4-c]pyrrole-1,3-diones

Guillermo Martinez-Ariza

^aDepartment of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA Fax: +1(520)6260794 eMail: hulme@pharmacy.arizona.edu

,

Justin Dietrich

^aDepartment of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA Fax: +1(520)6260794 eMail: hulme@pharmacy.arizona.edu

,

Fabio De Moliner

^aDepartment of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA Fax: +1(520)6260794 eMail: hulme@pharmacy.arizona.edu

,

Christopher Hulme*

^aDepartment of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA Fax: +1(520)6260794 eMail: hulme@pharmacy.arizona.edu

^bDepartment of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA

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Abstract

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Abstract

An efficient tandem [3+2] cycloaddition–elimination cascade sequence has been developed enabling assembly of the pharmacologically relevant pyrrolo-[3,4-c]pyrrole-1,3-dione chemotype. The strategy involves simple mixing of readily accessible oxazolin-2-ones and pyrrole-2,5-diones in the presence of base under mild conditions, rendering the title compounds in typically excellent yields. Of note, this route allows for installation of three points of diversity and is ideal for combinatorial applications and parallel synthesis production campaigns.

Key words

cycloaddition - elimination - tandem reaction - bicyclic compounds - ylides

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Referenzen

References and Notes
1 These two authors contributed equally to this work.

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14 Bergman J, Lidgren G. Tetrahedron Lett. 1989; 30: 4597
15 General Procedure for the Preparation of Compounds 1 (Route A), Exemplified for Compound 1b 3-Chlorophenylglycine (5.41 mmol, 1.0 g) was added to TFAA (3 mL) in a 25 mL round-bottomed flask. The mixture was stirred for 2 h at r.t. and excess TFAA was removed in vacuo by means of azeotroping with toluene (5 × 10 mL) to give 1.32 g (93% yield) of a yellow solid product. ¹H NMR (400 MHz, CDCl₃): δ = 8.42 (t, J = 1.8 Hz, 1 H), 8.37–8.34 (m, 1 H), 7.63 (ddd, J = 8.1, 2.1, 1.0 Hz, 1 H), 7.49 (t, J = 8.0 Hz, 1 H), 6.28 (q, J = 4.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 162.2, 159.8, 135.4, 134.0, 130.6, 130.4, 129.7, 128.9, 128.7, 127.2, 125.4, 121.6, 118.8, 92.4 (q, J _C–F = 35.5 Hz). MS: m/z = 264 [M + H]⁺.

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17 General Procedure for the Preparation of Compounds 1 (Route B), Exemplified for Compound 1d Phenylglycine (1.0 equiv, 6.60 mmol, 1.0 g) was added to 2.0 M NaOH (20 mL) in a 100 mL round-bottomed flask. The solution was cooled to 0 °C in an ice bath, and then 4-fluorobenzoylchloride (9, 1.0 equiv, 6.60 mmol, 0.78 mL) was added dropwise over 20 min. The reaction was allowed to warm to r.t. and stirred for 2 h. The solution was then made slightly acidic (pH 5–6) by dropwise addition of 2.0 M HCl and was extracted with EtOAc (5 × 75 mL). The organic phase was dried over MgSO₄ and concentrated in vacuo to yield 8d as white solid (1.6 g). ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.96 (s, 1 H), 9.06 (d, J = 7.4 Hz, 1 H), 7.99 (dd, J = 8.4, 6.0 Hz, 2 H), 7.50–7.46 (m, 2 H), 7.39–7.24 (m, 4 H), 5.58 (d, J = 7.4 Hz, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 172.3, 166.8, 166.6, 165.7, 163.7 (d, J _C–F = 87.9 Hz), 137.4, 132.5 (d, J _C–F = 12.4 Hz), 130.9 (d, J _C–F = 10.1 Hz), 130.6, 128.8, 128.6, 128.4, 127.8, 116.0 (d, J _C–F = 21.9 Hz), 115.5 (d, J _C–F = 21.8 Hz), 57.4. MS: m/z = 274 [M + H]⁺. Compound 8d (5.86 mmol, 1.6 g) was then added to Ac₂O (3 mL) in a 25 mL round-bottomed flask. The mixture was stirred for 2 h at r.t. and excess Ac₂O was removed in vacuo via azeotroping with toluene (5 × 10 mL) to give 1.36 g of a yellow solid product (81% yield over two steps). ¹H NMR (400 MHz, CDCl₃): δ = 8.15–8.07 (m, 2 H), 7.50–7.35 (m, 5 H), 7.28–7.13 (m, 2 H), 5.51 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.0, 166.9, 163.0 (d, J _C–F = 281.9 Hz), 133.3, 130.6 (d, J _C–F = 9.2 Hz), 129.0, 128.8, 128.2 (d, J _C–F = 8.6 Hz), 126.8, 121.9, 116.2 (d, J _C–F= 22.3 Hz), 115.9 (d, J _C–F = 22.2 Hz), 68.1. MS: m/z = 256 [M + H]⁺.

18a Dubernet M, Caubet V, Guillard J, Viaud-Massuard MC. Tetrahedron 2005; 61: 4585
18b Choi DS, Huang S, Huang M, Barnard TS, Adams RD, Seminario JM, Tour JM. J. Org. Chem. 1998; 63: 2646
18c Xie J, Lown JW. Tetrahedron Lett. 1994; 35: 5555

19 General Procedure for the Preparation of Compounds 2, Exemplified for Compound 2c 3-Bromomaleic anhydride (1.0 equiv, 5.65 mmol, 1.0 g) was dissolved in AcOH (20 mL). Methylamine hydrochloride (1.0 equiv, 5.65 mmol, 0.37 g) was then added, and the reaction was heated at 80 °C for 3 h. Solvent was removed in vacuo, and the crude mixture was purified by column chromatography over silica gel (EtOAc–hexane 0–30%) using an ISCO^TM purification system to afford 0.97 g of a white solid (90% yield). ¹H NMR (400 MHz, CDCl₃): δ = 6.89 (s,1 H), 3.08 (s,3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.5, 165.3, 131.9, 131.3, 24.6. MS: m/z = 191 [M + H]⁺.
20 General Procedure for the Preparation of Compounds 5, Exemplified for Compound 5a 4-Phenyl-2-(trifluoromethyl)oxazol-5(4H)-one (1a, 1.0 equiv, 1,3 mmol, 0.30 g) and 3-bromo-phenyl-1H-pyrrole-2,5-dione (2a, 1.0 equiv, 1,3 mmol, 0.33 g) were dissolved in toluene (20 mL). DIPEA (2.0 equiv, 2.6 mmol, 0.45 mL) was added. The reaction mixture was stirred at r.t. for 15 min. Solvent was evaporated in vacuo, and the crude material was purified by column chromatography over silica gel (EtOAc–Hexane 0–50%) using an ISCO^TM purification system to afford 0.44 g of a yellow solid (91% yield). Crystals suitable for X-ray diffraction studies were obtained by recrystallization of the pure product from CH₂Cl₂ and hexane. ¹H NMR (400 MHz, CDCl₃): δ = 7.41 (m, 10 H), 8.44 (s, 1 H). ¹³C NMR (100 MHZ, CDCl₃): δ = 166.4, 162.0, 134.6, 133.4, 132.8, 131.9, 130.3, 129.6, 129.2, 129.1, 128.5, 126.9, 125.9, 121.9, 119.0, 29.6 (m). MS: m/z = 357 [M + H]⁺.
21 Complete crystallographic information for compound 5a can be found in: Roberts SA, Martinez-Ariza G, Dietrich J, Hulme C. Acta Crystallogr., Sect. E: Struct. Rep. Online 2012; 68: 496