Cu(II)-Mediated One-Pot Alkoxide Conjugate Addition/Radical Cyclizations as a Versatile Method to Highly Functionalized Tetrahydrofuran Derivatives

Ullrich Jahn; Dmytro Rudakov

doi:10.1055/s-2004-822930

LETTER

Cu(II)-Mediated One-Pot Alkoxide Conjugate Addition/Radical Cyclizations as a Versatile Method to Highly Functionalized Tetrahydrofuran Derivatives

Ullrich Jahn*, Dmytro Rudakov
Institut für Organische Chemie, Technische Universität Braunschweig, Hagenring 30, 38106 Braunschweig, Germany
Fax: +49(531)3915388; e-Mail: u.jahn@tu-bs.de;

Abstract

All articles of this category

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

Full Text

References

For oxidative radical cyclizations from anions, see:

<A NAME="RG02604ST-1A">1a</A> Dalko PI. Tetrahedron 1995, 51: 7579

<A NAME="RG02604ST-1B">1b</A> Iqbal J. Bhatia B. Nayyar NK. Chem. Rev. 1994, 94: 519

<A NAME="RG02604ST-2A">2a</A> Jahn U. Chem. Commun. 2001, 1600

<A NAME="RG02604ST-2B">2b</A> Jahn U. Müller M. Aussieker S. J. Am. Chem. Soc. 2000, 122: 5212

<A NAME="RG02604ST-3">3</A> See for instance: Elliott MC. J. Chem. Soc., Perkin Trans. 1 2002, 2301 ; and earlier reviews in this series

Reviews:

<A NAME="RG02604ST-4A">4a</A> Balme G. Bouyssi D. Lomberget T. Monteiro N. Synthesis 2003, 2115

<A NAME="RG02604ST-4B">4b</A> Balme G. Bossharth E. Monteiro N. Eur. J. Org. Chem. 2003, 4101

<A NAME="RG02604ST-5A">5a</A> Durand AC. Rodriguez J. Dulcere JP. Synlett 2000, 731

<A NAME="RG02604ST-5B">5b</A> Durand A.-C. Dumez E. Rodriguez J. Dulcere J.-P. Chem. Commun. 1999, 2437

On prolonged heating of the nitronates 3 ^-, only some decomposition was observed.

For a few radical cyclizations of α-nitro radicals to carbocycles, see:

<A NAME="RG02604ST-7A">7a</A> Arai N. Narasaka K. Bull. Chem. Soc. Jpn. 1997, 70: 2525 ; and cited references

<A NAME="RG02604ST-7B">7b</A> Bowman WR. Brown DS. Burns CA. Crosby D. J. Chem. Soc., Perkin Trans. 1 1994, 2083

<A NAME="RG02604ST-7C">7c</A> Bowman WR. Brown DS. Burns CA. Crosby D. J. Chem. Soc., Perkin Trans. 1 1993, 2099

<A NAME="RG02604ST-7D">7d</A> Kende AS. Koch K. Tetrahedron Lett. 1986, 27: 6051

<A NAME="RG02604ST-8">8</A> For the addition of inorganic oxygen-centered radicals to alkynes, see: Wille U. Jargstorff C. J. Chem. Soc., Perkin Trans. 1 2002, 1036

<A NAME="RG02604ST-9">9</A> Review on conjugate additions to nitroalkenes: Berner OM. Tedeschi L. Enders D. Eur. J. Org. Chem. 2002, 1877

<A NAME="RG02604ST-10A">10a</A> Jiao X.-D. Espenson JH. Inorg. Chem. 2000, 39: 1549

<A NAME="RG02604ST-10B">10b</A> Schmidt SP. Basolo F. Trogler WC. Inorg. Chim. Acta 1987, 131: 181

<A NAME="RG02604ST-10C">10c</A> Freier RK. Aqueous Solutions Data for Inorganic and Organic Compounds Vol. 1: de Gruyter; Berlin, New York: 1976.

The presented values can only serve as a rough guideline, since our experimental conditions are completely different from those of the electrochemical measurements.

Commercial anhydrous CuCl₂ was heated to 130 °C for 48 h under high vacuum to remove traces of H₂O.

General 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).

Selected 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.

Configuration determined by NOE difference spectroscopy.

The relative configuration was proved by X-ray crystallography.

<A NAME="RG02604ST-16A">16a</A> Beckwith ALJ. Schiesser CH. Tetrahedron 1985, 41: 3925

<A NAME="RG02604ST-16B">16b</A> Spellmeyer DC. Houk KN. J. Org. Chem. 1987, 52: 959

<A NAME="RG02604ST-17">17</A> Curran DP. Porter NA. Giese B. Stereochemistry of Radical Reactions VCH; Weinheim: 1996.

<A NAME="RG02604ST-18A">18a</A> Kochi JK. In Free Radicals Vol. 1: Kochi JK. Wiley; New York: 1973. p.591-683

<A NAME="RG02604ST-18B">18b</A> Barton DHR. Jacob M. Peralez E. Tetrahedron Lett. 1999, 40: 9201

<A NAME="RG02604ST-19">19</A> In analogy to: Burke SD. Voight EA. Org. Lett. 2001, 3: 237

<A NAME="RG02604ST-20A">20a</A> In analogy to: Rozners E. Katkevica D. Bizdena E. Strömberg R. J. Am. Chem. Soc. 2003, 125: 12125

The crude amine was protected as usual with Boc₂O/Et₃N.