Subscribe to RSS
DOI: 10.1055/s-2007-985583
Nef Reaction of Nitropyrrolidines: Novel Synthesis of Hydroxypyrrolidine Derivatives
Publication History
Publication Date:
13 August 2007 (online)
![](https://www.thieme-connect.de/media/synlett/200715/lookinside/thumbnails/10.1055-s-2007-985583-1.jpg)
Abstract
A general synthetic route to hydroxypyrrolidine derivatives using the first Nef reaction of nitropyrrolidines with chromium(II) chloride as a key step is presented.
Key words
cycloadditions - heterocycles - Nef reaction - pyrrolidines - reductions
-
1a
Johnson JH.Phillipson DW.Kahle AD. J. Antibiot. 1989, 42: 1184 -
1b
Kasahara K.Yoshida M.Eishima J.Takesako K.Beppu T.Horinouchi S. J. Antibiot. 1997, 50: 267 - 2
Achenbach TV.Slater PE.Brummerhop H.Bach T.Müller R. Antimicrob. Agents Chemother. 2000, 44: 2794 - 3
Jimènez A.Vázquez D. In Antibiotics, Anisomycin and Related Antibiotics Part 2, Vol. 5:Hahn FE. Springer-Verlag; New York: 1979. p.1-19 - 4
Kim JH.Curtis-Long MJ.Seo WD.Ryu Y.-B.Yang MS.Park KH. J. Org. Chem. 2005, 70: 4082 ; and references cited therein - 5
Reddy JS.Rao BV. J. Org. Chem. 2007, 72: 2224 ; and references cited therein -
6a
El Ashry ESH.Rashed N.Shobier AHS. Pharmazie 2000, 55: 331 -
6b
Lombardo M.Fabbroni S.Trombini C. J. Org. Chem. 2001, 66: 1264 -
6c
Yoda H. Curr. Org. Chem. 2002, 6: 223 - 7
Giovannini R.Marcantoni E.Petrini M. J. Org. Chem. 1995, 60: 5706 -
8a
Nemr AE. Tetrahedron 2000, 56: 8579 -
8b
Guo H.O’Doherty GA. Org. Lett. 2006, 8: 1609 -
9a
Pak CS.Nyerges M. Bull. Korean Chem. Soc. 1999, 20: 633 -
9b
Pak CS.Nyerges M. Synlett 1999, 1271 -
9c
Fejes I.Nyerges M.Tõke L.Pak CS. Tetrahedron 2000, 56: 639 -
9d
Nyerges M.Rudas M.Tóth G.Herényi B.Kádas I.Bitter I.T L. Tetrahedron 1995, 51: 13321ke -
9e
Ayerbe M.Arrieta A.Cossio FP.Linden A. J. Org. Chem. 1998, 63: 1795 -
9f
Fejes I.Nyerges M.Blaskó G.Tõke L.Pak CS. Tetrahedron 2000, 43: 8545 -
10a
Noland WE. Chem. Rev. 1955, 55: 137 -
10b
McMurry JE.Melton J. J. Org. Chem. 1973, 38: 4367 -
10c
Ballini R.Petrini M. Tetrahedron 2004, 60: 1017 - 11
Olah GA.Arvanaghi M.Vankar YD.Prakash GKS. Synthesis 1980, 662 - 13 Hassner A., Heathcock C.; J. Org. Chem.;
1964,
29: 1350
References and Notes
General Procedure for the Preparation of Compounds 8: The appropriate pyrrolidine derivative 7 (10 mmol) was dissolved in anhyd CH2Cl2 (30 mL) and pyridine (1 mL) was added. The solution was cooled to 0 °C and then methyl chloroformate (1.13 g, 0.93 mL, 12 mmol) was added. The orange mixture was stirred for another 16 h, allowing the temperature to rise to r.t. The reaction mixture was extracted with dilute HCl and aq NaHCO3, dried over MgSO4, and the solvent was evaporated to yield the product which was purified by recrystallization from Et2O.
14
General Procedure for Nef Reaction of 8a-h: Potassium dichromate dihydrate (2.0 g) was dissolved in 6 M HCl acid (30 mL) and zinc powder (3.3 g) was added under an argon atmosphere. After the complete dissolution of zinc the formed chromium(II) chloride solution was transferred via syringe to the refluxing solution of nitro compound (1 mmol) in MeOH (30 mL) under argon. After 1 h reflux, the reaction mixture was cooled and evaporated to half of its volume. It was extracted with CH2Cl2. The organic phase was washed with aq NaHCO3 solution, brine, dried over MgSO4, then evaporated to yield a colorless oil, which was further purified by column chromatography.
Selected data for representative examples are as follows:
2-Ethoxycarbonyl-1-methoxycarbonyl-5-(4-methoxy-phenyl)pyrrolidine-4-one (9b): pale yellow oil. 1H NMR (300 MHz, CDCl3): δ = 7.49 (dd, J = 8.9 Hz, 2 H, 2′-Ar, 6′-H), 6.95 (dd, J = 8.9 Hz, 2 H, 2′-Ar, 6′-H), 4.95 (br s, 1 H, H-5), 4.88 (dd, J = 3.5, 5.7 Hz, 1 H, H-2), 4.25 (q, J = 7.1 Hz, 2 H, OCH2), 3.83 (s, 3 H, OMe), 3.69 (br s, 3 H, OMe), 3.00 (br dd, J = 3.5, 18.0 Hz, 1 H, H-3), 2.77 (dd, J = 5.7, 18.0 Hz, 1 H, H-3), 1.35 (t, 3 H, Me). 13C NMR (75 MHz, CDCl3): δ = 206.3 (q), 171.9 (q), 159.4 (q), 157.0 (q), 126.7 (2 × CH), 114.2 (2 × CH), 66.0 (CH), 61.6 (CH2), 55.5 (CH), 55.2 (Me), 52.8 (Me), 38.6 (CH2), 14.2 (Me).
2-Ethoxycarbonyl-1-methoxycarbonyl-3-(4-methoxy-phenyl)-5-phenylpyrrolidine-4-one (9f): 1H NMR (300 MHz, CDCl3): δ = 7.67 (d, J = 7.5 Hz, 2 H, 2′-Ph, 6′-H), 7.38 (t, J = 7.5 Hz, 2 H, 3′-Ph, 5′-H), 7.30 (t, 1 H, 4′-Ph), 7.06 (d, J = 8.6 Hz, 2 H, 3′-Ar, 5′-H), 6.86 (d, J = 8.6 Hz, 2 H, 2′-Ar, 6′-H), 5.11 (br s, 1 H, H-5), 4.72 (d, J = 8.6 Hz, 1 H, H-3), 4.25 (q, J = 7.1 Hz, 2 H, OCH2), 3.94 (d, J = 8.6 Hz, 1 H, H-2), 3.76 (s, 3 H, ArOMe), 3.62 (br s, 3 H, CO2Me), 1.24 (t, 3 H, Me). 13C NMR (75 MHz, CDCl3): δ = 204.9 (q), 171.2 (q), 159.4 (q), 136.1 (q), 131.1 (q), 129.4 (2 × CH), 128.7 (2 × CH), 128.3 (CH), 126.0 (2 × CH), 125.0 (q), 114.4 (2 × CH), 77.2 (CH), 66.5 (CH), 63.0 (CH), 61.7 (CH2), 55.2 (Me), 53.3 (Me), 14.1 (Me).
General Procedure for Reduction of 9a-h: LiAlH4 (0.4 g, 10 mmol) was suspended in anhyd THF (5 mL) under an argon atmosphere. A solution of ketopyrrolidine 9 (2 mmol) in anhyd THF (5 mL) was added via syringe. The reaction mixture was heated under reflux for 2 h and then cooled. EtOAc (2 mL) and sat. aq NH4Cl solution (4 mL) were added. The precipitate was filtered off and washed with Et2O. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo to yield a waxy solid. In the cases when a mixture of two diastereomer was obtained, the mixture was separated by column chromatography.
Selected data for representative examples are as follows:
4-Hydroxy-2-hydroxymethyl-5-(4-methoxyphenyl)-1-methylpyrrolidine (11b): 1H NMR (500 MHz, CDCl3): δ = 7.30 (d, J = 8.6 Hz, 2 H, 2′-Ar, 6′-H), 6.90 (d, J = 8.6 Hz, 2 H, 3′-Ar, 5′-H), 4.02 (t, J = 4.1 Hz, 1 H, H-4), 3.80 (s, 3 H, OMe), 3.76 (dd, J = 2.8, 10.8 Hz, 1 H, OCH2), 3.50 (d, J = 4.1 Hz, 1 H, H-5), 3.47 (dd, J = 1.8, 10.8 Hz, 1 H, OCH2), 2.75 (dddd, J = 0.9, 1.8, 2.8, 6.1 Hz, 1 H, H-2), 2.38 (ddd, J = 4.2, 6.1, 14.2 Hz, 1 H, H-3), 1.91 (ddd, J = 0.9, 4.6, 14.2 Hz, 1 H, H-3), 2.21 (s, 3 H, NMe). 13C NMR (125 MHz, CDCl3): δ = 159.0(q), 129.4 (2 × CH), 113.7 (2 × CH), 76.2 (CH), 72.9 (CH), 64.8 (CH), 61.5 (CH2), 55.1 (Me), 38.1 (Me), 35.6 (CH2). IR (neat): 3359, 2943, 2787, 1612, 1513, 1443, 1246, 1173, 1034 cm-1.
4-Hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)-1-methyl-5-phenylpyrrolidine (Major Isomer) (10f): 1H NMR (500 MHz, CDCl3): δ = 7.39 (d, J = 7.8 Hz, 2 H, 2′-Ph, 6′-H), 7.35 (t, J = 7.8 Hz, 2 H, 3′-Ph, 5′-H), 7.29 (t, J = 7.8 Hz, 1 H, 4′-Ph), 7.26 (d, J = 8.5 Hz, 2 H, 2′-Ar, 6′-H), 6.87 (d, J = 8.5 Hz, 2 H, 3′-Ar, 5′-H), 4.10 (dd, J = 3.3, 5.8 Hz, 1 H, H-4), 3.83 (d, J = 5.8 Hz, 1 H, H-5), 3.78 (s, 3 H, OMe), 3.77 (dd, J = 2.8, 11.3 Hz, 1 H, OCH2), 3.49 (dd, J = 1.3, 11.3 Hz, 1 H, OCH2), 3.29 (dd, J = 3.3, 7.8 Hz, 1 H, H-3), 2.66 (ddd, J = 1.3, 2.7, 7.8 Hz, 1 H, H-2), 2.26 (s, 3 H, NMe). 13C NMR (125 MHz, CDCl3): δ = 158.3 (q), 137.2 (q), 133.7 (q), 129.0 (2 × CH), 128.8 (2 × CH), 128.4 (2 × CH), 114.2 (2 × CH), 79.5 (CH), 75.8 (CH), 73.0 (CH), 58.8 (CH), 55.2 (Me), 53.3 (Me), 38.5 (CH2). IR (KBr): 3425, 2956, 2914, 2802, 1612, 1513, 1470, 1450, 1401, 1341, 1302, 1261, 1246, 1064, 1030 cm-1.
Minor Isomer (11f): 1H NMR (500 MHz, CDCl3): δ = 7.45 (t, J = 7.6 Hz, 2 H, 3′-Ph, 5′-H), 7.36 (m, 4 H, Ar), 7.29 (t, 1 H, 4′-Ph), 6.84 (d, J = 8.8 Hz, 2 H, 3′-Ar, 5′-H), 4.19 (t, J = 3.4 Hz, 1 H, H-4), 3.91 (d, J = 3.3 Hz, 1 H, H-5), 3.77 (s, 3 H, OMe), 3.71 (dd, J = 3.9, 10.3 Hz, 1 H, H-3), 3.58 (dd, J = 3.7, 11.4 Hz, 1 H, OCH2), 3.39 (dd, J = 1.8, 11.4 Hz, 1 H, OCH2), 3.22 (ddd, J = 1.8, 3.7, 10.3 Hz, 1 H, H-2), 2.41 (s, 3 H, NMe). 13C NMR (125 MHz, CDCl3): δ = 158.9 (q), 137.9 (q), 136.5 (q), 130.3 (2 × CH), 128.4 (2 × CH), 128.3 (2 × CH), 113.6 (2 × CH), 77.7 (CH), 76.0 (CH), 70.0 (CH), 57.1 (CH), 55.1 (Me), 54.4 (Me), 38.3 (CH2). IR (neat): 3428, 2959, 2810, 1615, 1517, 1472, 1450, 1408, 1342, 1249, 1060 cm-1.