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DOI: 10.1055/s-2004-822930
Cu(II)-Mediated One-Pot Alkoxide Conjugate Addition/Radical Cyclizations as a Versatile Method to Highly Functionalized Tetrahydrofuran Derivatives
Publication History
Publication Date:
10 May 2004 (online)
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Abstract
The synthesis of highly functionalized 3-nitrotetrahydrofurans starting from allylic alcohols and nitroalkenes through an efficient CuCl2-mediated tandem anionic/radical process is reported. The one-pot reaction consists of oxa-Michael addition/SET/radical 5-exo-cyclization-ligand transfer. Functionalization of the THF ring is facile and provides diverse substituted derivatives.
Key words
cyclizations - electron transfer - Michael addition - radicals - tandem reactions
- For oxidative radical cyclizations from anions, see:
-
1a
Dalko PI. Tetrahedron 1995, 51: 7579 -
1b
Iqbal J.Bhatia B.Nayyar NK. Chem. Rev. 1994, 94: 519 -
2a
Jahn U. Chem. Commun. 2001, 1600 -
2b
Jahn U.Müller M.Aussieker S. J. Am. Chem. Soc. 2000, 122: 5212 - 3 See for instance:
Elliott MC. J. Chem. Soc., Perkin Trans. 1 2002, 2301 ; and earlier reviews in this series - Reviews:
-
4a
Balme G.Bouyssi D.Lomberget T.Monteiro N. Synthesis 2003, 2115 -
4b
Balme G.Bossharth E.Monteiro N. Eur. J. Org. Chem. 2003, 4101 -
5a
Durand AC.Rodriguez J.Dulcere JP. Synlett 2000, 731 -
5b
Durand A.-C.Dumez E.Rodriguez J.Dulcere J.-P. Chem. Commun. 1999, 2437 - For a few radical cyclizations of α-nitro radicals to carbocycles, see:
-
7a
Arai N.Narasaka K. Bull. Chem. Soc. Jpn. 1997, 70: 2525 ; and cited references -
7b
Bowman WR.Brown DS.Burns CA.Crosby D. J. Chem. Soc., Perkin Trans. 1 1994, 2083 -
7c
Bowman WR.Brown DS.Burns CA.Crosby D. J. Chem. Soc., Perkin Trans. 1 1993, 2099 -
7d
Kende AS.Koch K. Tetrahedron Lett. 1986, 27: 6051 - 8 For the addition of inorganic oxygen-centered radicals to alkynes, see:
Wille U.Jargstorff C. J. Chem. Soc., Perkin Trans. 1 2002, 1036 - 9 Review on conjugate additions to nitroalkenes:
Berner OM.Tedeschi L.Enders D. Eur. J. Org. Chem. 2002, 1877 -
10a
Jiao X.-D.Espenson JH. Inorg. Chem. 2000, 39: 1549 -
10b
Schmidt SP.Basolo F.Trogler WC. Inorg. Chim. Acta 1987, 131: 181 -
10c
Freier RK. Aqueous Solutions Data for Inorganic and Organic Compounds Vol. 1: de Gruyter; Berlin, New York: 1976. -
10d
The presented values can only serve as a rough guideline, since our experimental conditions are completely different from those of the electrochemical measurements.
-
16a
Beckwith ALJ.Schiesser CH. Tetrahedron 1985, 41: 3925 -
16b
Spellmeyer DC.Houk KN. J. Org. Chem. 1987, 52: 959 - 17
Curran DP.Porter NA.Giese B. Stereochemistry of Radical Reactions VCH; Weinheim: 1996. -
18a
Kochi JK. In Free Radicals Vol. 1:Kochi JK. Wiley; New York: 1973. p.591-683 -
18b
Barton DHR.Jacob M.Peralez E. Tetrahedron Lett. 1999, 40: 9201 - 19 In analogy to:
Burke SD.Voight EA. Org. Lett. 2001, 3: 237 -
20a In analogy to:
Rozners E.Katkevica D.Bizdena E.Strömberg R. J. Am. Chem. Soc. 2003, 125: 12125 -
20b
The crude amine was protected as usual with Boc2O/Et3N.
References
On prolonged heating of the nitronates 3 -, only some decomposition was observed.
11Commercial anhydrous CuCl2 was heated to 130 °C for 48 h under high vacuum to remove traces of H2O.
12General Procedure: At -78 °C under N2, 1.5 mmol of n-BuLi (1,6 M solution in hexane) was added via syringe to a stirred solution of allylic alcohols 2a-e (1.5 mmol) in dry DME (10 mL). After 15 min, a solution of nitroalkene 1a or b (1 mmol) in dry DME (1 mL) was added. The reaction mixture was warmed slowly from -50 to -40 °C and maintained at this temperature until completed by TLC. After changing to an ice bath, 471 mg (3.5 mmol) of anhyd CuCl2 was added in one portion with vigorous stirring. After 30 min, the reaction was quenched with a sat. solution of NH4Cl (1 mL). The inhomogeneous green-brown solution was diluted with Et2O (20 mL) and filtered through a silica gel pad. The solution was concentrated to 5 mL, silica gel (2 g) was added and the remaining solvent was removed under vacuum. The thus pre-adsorbed crude product was purified by silica gel flash column chromatography with hexane/EtOAc (gradient: 40:1 to 1:1).
13Selected spectral data: Compound 5aa: IR (film): 3070, 3049, 3033, 3016, 2978, 2970, 2958, 1549, 1381, 1098, 1072, 742, 701 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.37-7.27 (m, 5 H, Ph), 5.49 (d, J = 3.1 Hz, 1 H, CHPh), 5.01 (dd, J = 7.4, 3.1 Hz, 1 H, CHNO2), 4.44 (t, J = 8.4 Hz, 1 H, OCH2), 4.05 (dd, J = 10.3, 8.7 Hz, 1 H, OCH2), 3.60 (dd, J = 11.3, 7.4 Hz, 1 H, CH2Cl), 3.50 (dd, J = 11.3, 8.1 Hz, 1 H, CH2Cl), 3.04 (d quint, J = 10.3, 7.5 Hz, 1 H, CHCH2Cl). 13C NMR (100 MHz, CDCl3): δ = 138.4 (s, Ph), 128.8 (d, Ph), 128.7 (d, p-Ph), 125.2 (d, Ph), 93.2 (d, CHNO2), 84.9 (d, CHPh), 71.2 (t, CH2O), 45.6 (d, CHCH2Cl), 39.3 (t, CH2Cl). MS (CI): m/z (%) = 278/276 (7/22), 261/259 (45/100) [M + NH4]+, 225 (38), 208 (25), 195 (7), 145 (18). Compound 6aa: mp 68 °C. 1H NMR (400 MHz, CDCl3): δ = 7.30-7.25 (m, 5 H, Ph), 5.19 (dd, J = 6.2, 2.9 Hz, 1 H, CHNO2), 5.12 (d, J = 6.3 Hz, 1 H, CHPh), 4.53 (dd, J = 8.9, 8.1 Hz, 1 H, OCH2), 3.72 (dd, J = 9.0, 7.2 Hz, 1 H, OCH2), 3.63 (dd, J = 8.1, 6.0 Hz, 1 H, CH2Cl), 3.52 (m, 2 H, CH2Cl, CHCH2Cl). 13C NMR (100 MHz, CDCl3): δ = 133.8 (s, Ph), 128.8 (d, Ph), 128.3 (d, Ph), 125.9 (d, Ph), 92.8 (d, CHNO2), 83.7 (d, CHPh), 70.1 (t, CH2O), 46.3 (d, CHCH2Cl), 43.0 (t, CH2Cl). MS (CI): m/z (%) = 278/276 (5/15) [M + NH3 + NH4]+, 261/259 (30/100) [M + NH4]+, 225 (30), 195 (22). Anal. Calcd for C11H12ClNO3 (241.7): C, 54.67; H, 5.00; N, 5.80. Found: C, 54.84; H, 4.91; N, 5.65. Compound 5ab: mp 110 °C. IR (KBr): 3089, 3064, 3031, 3019, 2995, 2979, 2905, 1548, 1378, 1137, 1103, 1073, 724, 699 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.39-7.27 (m, 5 H, Ph), 5.58 (br s, 1 H, CHPh), 4.97 (dd, J = 6.1, 1.2 Hz, 1 H, CHNO2), 4.49 (t, J = 8.2 Hz, 1 H, CH2O), 4.45 (dd, J = 11.2, 8.3 Hz, 1 H, CH2O), 2.85 (ddd, J = 11.3, 7.8, 6.2 Hz, 1 H, CHCCl), 1.62 (s, 3 H, CH3), 1.60 (s, 3 H, CH3). 13C NMR (100 MHz, CDCl3): δ = 139.4 (s, Ph), 128.9 (d, Ph), 128.5 (d, p-Ph), 125.1 (d, Ph), 92.2 (d, CHNO2), 85.1 (d, CHPh), 69.1 (t, CH2O), 65.7 (s, CCl), 55.3 (d, CHCCl), 32.2 (q, CH3), 30.3 (q, CH3). MS (CI): m/z (%) = 306/304 (3/10) [M + NH3 + NH4]+, 289/287 (24/100) [M + NH4]+, 271 (10), 254 (20), 237 (23), 220 (23), 202 (19), 145 (7). Anal. Calcd for C13H16ClNO3 (269.7): C, 57.89; H, 5.98; N, 5.19. Found: C, 58.19; H, 6.12; N, 4.93. Compound 5bb: IR (film): 2972, 2935, 2897, 1552, 1375, 1131, 1101, 1057, 779 cm-1. 1H NMR (400 MHz, CDCl3): δ = 4.81 (dd, J = 6.4, 1.6 Hz, 1 H, CHNO2), 4.39 (dt, J = 7.0, 1.4 Hz, 1 H, CHEt), 4.24 (dd, J = 11.2, 8.4 Hz, 1 H, CH2O), 4.20 (dd, J = 8.2, 7.4 Hz, 1 H, CH2O), 2.80 (dt, J = 11.3, 7.1 Hz, 1 H, CHCCl), 1.64 (s, 3 H, CH3), 1.61 (s, 3 H, CH3), 1.59 (m, 1 H, CH2CH3), 1.49 (sext, J = 7.2 Hz, 1 H, CH 2CH3), 0.95 (t, J = 7.4 Hz, 3 H, CH 3CH2). 13C NMR (100 MHz, CDCl3): δ = 89.6 (d, CHNO2), 85.7 (d, CHEt), 68.2 (t, CH2O), 65.8 (s, CCl), 56.8 (d, CHCCl), 31.8 (q, CH3CCl), 30.6 (q, CH3CCl), 28.4 (t, CH3 CH2), 9.7 (q, CH3CH2). MS (CI): m/z (%) = 239 (1) [M + NH4]+, 203 (18), 189 (10), 172 (10), 156 (16), 139 (100). Anal. Calcd for C9H16ClNO3 (221.7): C, 48.76; H, 7.27; N, 6.32. Found: C, 48.81; H, 7.27; N, 6.09.
14Configuration determined by NOE difference spectroscopy.
15The relative configuration was proved by X-ray crystallography.