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

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.

cyclizations - electron transfer - Michael addition - radicals - tandem reactions

References

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 

6

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

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.

11

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

12

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).

13

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.

14

Configuration determined by NOE difference spectroscopy.

15

The relative configuration was proved by X-ray crystallography.

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.