2-Diethoxyphosphoryl-4-nitroalkanoates - Versatile Intermediates in the ­Synthesis of α-Alkylidene-γ-lactones and Lactams

Abstract

Michael addition of various nitroalkanes 7a-f to ethyl (2-diethoxyphosphoryl)acrylate (6) gave 2-diethoxyphosphoryl-4-nitroalkanoates 8a-f. Transformation of the nitro functionality into hydroxy or amino group and cyclization yielded 3-(diethoxyphosphoryl)tetrahydro-2-furanones 11a-e or 3-(diethoxyphosphoryl)pyrrolidin-2-ones 14a-e, respectively. These compounds were then used in Horner-Wadsworth-Emmons olefinations of aldehydes to give 3-alkylidenedihydrofuran-2-ones 12a-e or 17a-c and 3-methylidenepyrrolidin-2-ones 15a-e.

Michael addition - nitroalkanoates - Wittig type olefination - α-alkylidenelactones - α-methylidenelactams

References

<A NAME="RG29904ST-1">1</A> Hoffmann HMR. Rabe J. Angew. Chem., Int. Ed. Engl.  1985,  24:  94 

<A NAME="RG29904ST-2">2</A> Paquette LA. Mendez-Andino J. Tetrahedron Lett.  1999,  40:  4301 ; and references cited therein

<A NAME="RG29904ST-3">3</A> Steurer S. Podlech J. Eur. J. Org. Chem.  2002,  899 ; and references cited therein

<A NAME="RG29904ST-4">4</A> Kang S.-K. Kim K.-J. Hong Y.-T. Angew. Chem. Int. Ed.  2002,  1584 ; and references cited therein

<A NAME="RG29904ST-5">5</A> Basavaiah D. Rao PD. Hyma RS. Tetrahedron  1996,  52:  8001 

<A NAME="RG29904ST-6">6</A> Bauchet R. Le Rouille E. Foucaud A. Bull. Soc. Chim. Fr.  1991,  128:  267 

<A NAME="RG29904ST-7">7</A> Ballini R. Bosica G. Livi D. Synthesis  2001,  1519 

<A NAME="RG29904ST-8">8</A> Basavaiah D. Rao JS. Tetrahedron Lett.  2004,  45:  1621 

<A NAME="RG29904ST-9">9</A> Janecki T. Błaszczyk E. Synthesis  2001,  403 

<A NAME="RG29904ST-10A">10a</A>

Prepared in 73% yield by modified literature procedure. [10b] A mixture of 36% formaline (28 mL, 0,30 mol), piperidine (1 mL) and MeOH (450 mL) was refluxed for 0.5 h. To this mixture was added triethyl phosphono-acetate (30.0 g 0.13 mol) in one portion at 25 °C and the mixture was heated at reflux for 70 h. After 20 h and 48 h additional portions of piperidine (0.5 mL) were added. Progress of the reaction was monitored by ³¹P NMR. The solution was cooled and concentrated by rotatory evaporation, the residue was extracted with CCl₄ (3 × 100 mL), combined extracts were dried (MgSO₄), evaporated and 85% H₃PO₄ (3 mL) was added to the residue which was distilled in high vacuum (85-87 °C/0.4 Torr) to give pure ethyl 2-(diethoxyphosphory)lacrylate (6, 22.4 g; 73%).

<A NAME="RG29904ST-10B">10b</A> Semmelhack MF. Tomesh JC. Czarny M. Boettger S. J. Org. Chem.  1978,  43:  1259 

<A NAME="RG29904ST-11">11</A>

General Procedure for the Preparation of Ethyl 2-diethoxyphosphoryl-4-nitroalkanoates 8a-f. A solution of nitroalkane 7 (17.0 mmol) in THF (10 mL) was added to a stirred suspension of NaH (0.213 g; 8.9 mmol) in THF (40 mL) under argon atmosphere at 0-4 °C. The reaction mixture was stirred for 40 min at r.t., cooled to 0-4 °C, and a solution of ethyl 2-diethoxyphosphorylacrylate (6) (2.000 g; 8.5 mmol) in THF (10 mL) was added. The mixture was then stirred for 24 h at r.t., THF was evaporated off at r.t. and the residue was quenched with H₂O (15 mL) and extracted with CH₂Cl₂ (4 × 20 mL). The organic extracts were dried (MgSO₄) and evaporated at r.t., to give a crude product, which was purified by column chromatography (silica gel, eluent CHCl₃-acetone = 90:10 for 8a-c, CHCl₃-acetone = 95:5 for 8d,e and EtOAc-hexane = 95:5 for 8f). Spectroscopic data for ethyl 2-diethoxyphosphoryl-5-(3,4-dimethoxyphenyl)-4-nitropentanoate (8e); dr 65:35. IR (film): 1732, 1552, 1260 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.28 (t, ³ J _HH = 7.0 Hz, 3 H, major + minor), 1.31 (t, ³ J _HH = 7.0 Hz, 3 H, major), 1.32 (td, ³ J _HH = 7.2 Hz, ⁴ J _PH = 0.5 Hz, 3 H, minor), 1.33 (td, ³ J _HH = 7.5 Hz, ⁴ J _PH = 0.5 Hz, 3 H, major), 1.34 (td, ³ J _HH = 7.0 Hz, ⁴ J _PH = 0.5 Hz, 3 H, minor), 2.28-2.75 (m, 2 H, major + minor), 2.84 (m, 1 H, major + minor), 3.02 (dd, ² J _HH = 14.5 Hz, ³ J _HH = 7.2 Hz, 1 H, minor), 3.03 (dd, ² J _HH = 14.5, ³ J _HH = 5.5 Hz, 1 H, major), 3.22 (dd, ² J _HH = 14.5 Hz, ³ J _HH = 8.8 Hz, 1 H, major), 3.23 (dd, ² J _HH = 14.5 Hz, ³ J _HH = 7.5 Hz, 1 H, minor), 3.85 (s, 3 H, major + minor), 3.86 (s, 3 H, major + minor), 4.02-4.28 (m, 4 H, major + minor), 4.67-4.81 (m, 1 H, major), 4.90-5.03 (m, 1 H, minor), 6.62-6.82 (m, 3 H, major + minor). ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.82 (s), 16.07 (d, ³ J _PC = 6.0 Hz), 30.04 (d, ² J _PC = 4.5 Hz), 30.26 (d, ² J _PC = 3.5 Hz), 39.46 (s), 39.60 (s), 41.77 (d, ¹ J _PC = 130.2 Hz), 42.06 (d, ¹ J _PC = 130.6 Hz), 55.67 (s), 55.70 (s), 61.76 (s), 61.82 (s), 62.99 (d, ² J _PC = 6.5 Hz), 87.39 (d, ³ J _PC = 8.4 Hz), 87.67 (d, ³ J _PC = 15.0 Hz), 111.26 (s), 111.73 (s), 111.81 (s), 120.88 (s), 121.02 (s), 127.10 (s), 148.28 (s), 148.93 (s), 167.58 (d, ² J _PC = 5.7 Hz), 167.73 (d, ² J _PC = 6.3 Hz). ³¹P NMR (101 MHz, CDCl₃): δ = 20.46 (major), 21.12 (minor). Anal. Calcd for C₁₉H₃₀NO₉P: C, 51.00; H, 6.76; N, 3.13; P, 6.92. Found: C, 51.12; H, 6.69; N, 3.20; P, 6.80.

<A NAME="RG29904ST-12">12</A> Villieras J. Rambaud M. Synthesis  1984,  406 

<A NAME="RG29904ST-13">13</A>

General Procedure for the Preparation of 3-Methylidenedihydrofuran-2-ones 12a-e. A mixture of 3-(diethoxyphosphoryl)tetrahydrofuran-2-one 11 (1.0 mmol), K₂CO₃ (0.415 g; 3.0 mmol) and 36% formaline (0.54 mL; 7.0 mmol) was stirred at 0-4 °C for 15 min. The mixture was extracted with Et₂O (4 × 15 mL), dried (MgSO₄) and evaporated. Residue was purified by column chromato-graphy (silica gel, eluent CHCl₃) to give 12. Spectroscopic data for 5-(3,4-dimethoxyphenylmethyl)-3-methylidene-dihydrofuran-2-one (12e). IR (film): 1772, 1664 cm^-1.
¹H NMR (250 MHz, CDCl₃): δ = 2.59 (ddt, ² J _HH = 17.0 Hz, ³ J _HH = 6.0 Hz, ⁴ J _HH = 2.8 Hz, 1 H), 2.81 (dd, ² J _HH = 14.3 Hz, ³ J _HH = 6.0 Hz, 1 H), 2.89 (ddt, ² J _HH = 17.0 Hz, ³ J _HH = 7.8 Hz, ⁴ J _HH = 2.8 Hz, 1 H), 2.95 (dd, ² J _HH = 14.3 Hz, ³ J _HH = 6.0 Hz, 1 H), 3.79 (s, 3 H), 3.80 (s, 3 H), 4.69 (dq, ³ J _HH = 7.8 Hz, ³ J _HH = 6.0 Hz, 1 H), 5.49 (t, ⁴ J _HH = 2.8 Hz, 1 H), 6.10 (t, ⁴ J _HH = 2.8 Hz, 1 H), 6.65-6.78 (m, 3 H). ¹³C NMR (62.9 MHz, CDCl₃): δ = 32.50 (s), 41.27 (s), 55.90 (s), 55.92 (s), 77.21 (s), 111.32 (s), 112.74 (s), 121.68 (s), 127.89 (s), 148.14 (s), 149.02 (s), 121.98 (s), 134.37 (s), 170.13 (s). Anal. Calcd for C₁₄H₁₆O₄: C, 67.73; H, 6.50. Found: C, 67.88; H, 6.41.

<A NAME="RG29904ST-14">14</A>

General Procedure for the Preparation of 3-Methylidenepyrrolidin-2-ones 15a-e. A solution of 3-(diethoxyphosphoryl)pyrrolidin-2-one 14 (1.00 mmol) in THF (7.0 mL) was added to a suspension of NaH (0.025 g; 1.05 mmol) in THF (3 mL) and the reaction mixture was stirred at r.t. for 30 min. Next, paraformaldehyde (0.033 g, 1.10 mmol) was added in one portion, the mixture was refluxed for 1 h and cooled to 0-4 °C. Then H₂O (3 mL) was added, THF was evaporated under reduced pressure and the residue was extracted with CH₂Cl₂ (3 × 15 mL). Combined organic extracts were washed with H₂O (5 mL), dried (MgSO₄) and evaporated to give crude 15, which were purified by column chromatography (silica gel, eluent CHCl₃). Spectroscopic data for 5-(3,4-dimethoxyphenyl-methyl)-3-methylidenepyrrolidin-2-one (15e). IR (film): 3100, 1684, 1662 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 2.45 (ddt, ² J _HH = 17.0 Hz, ³ J _HH = 4.0 Hz, ⁴ J _HH = 2.2 Hz, 1 H), 2.73 (ddt, ² J _HH = 17.0 Hz, ³ J _HH = 7.5 Hz, ⁴ J _HH = 2.2 Hz, 1 H), 2.82 (dd, ² J _HH = 13.8 Hz, ³ J _HH = 7.6 Hz, 1 H), 3.15 (dd, ² J _HH = 13.8 Hz, ³ J _HH = 3.4 Hz, 1 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 4.02-4.20 (m, 1 H), 5.18 (t, ⁴ J _HH = 2.2 Hz, 1 H), 5.83 (t, ⁴ J _HH = 2.2 Hz, 1 H), 6.53-6.57 (m, 3 H). ¹³C NMR (62.9 MHz, CDCl₃): δ = 28.13 (s), 37.41 (s), 55.81 (s), 58.20 (s), 115.92 (s), 111.14 (s), 112.69 (s), 121.72 (s), 128.17 (s), 147.89 (s), 148.93 (s), 135.58 (s), 163.89 (s). Anal. Calcd for C₁₃H₁₅NO₃: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.09; H, 6.57, N, 5.83.

<A NAME="RG29904ST-15">15</A> Macomber RSA. Complete Introduction to Modern NMR Spectroscopy   John Wiley and Sons; New York: 1998.  p.416