Catalyst-Free Microwave-Assisted Synthesis of α-Aminophosphonates in a Three-Component System: R¹C(O)R²-(EtO)₂P(O)H-RNH₂

Abstract

An effective catalyst-free microwave-assisted synthesis of α-aminophosphonates from ketones in a three-component system was shown. The method affords α-aminophosphonates in high yields from various ketones including natural porphyrine derivatives.

Key words

α-aminophosphonates - α-aminophosphonic acid - ketones - natural porphyrin - steroid

References

• 1 Kaboudin B. Nazari R. Tetrahedron Lett.  2001,  42:  8211 
• 2 Matveeva ED. Podrugina TA. Tishkovskaya EV. Tomilova LG. Zefirov NS. Synlett  2003,  2321 
• 3 Pavlov VYa. Kabachnik MM. Zobnina EV. Ponomarev GV. Beletskaya IP. Synlett  2003,  2193 
• 4 Fields SC. Tetrahedron  1999,  55:  12237 
• 5 Kleszczynska H. Sarapuk J. Cell. Mol. Biol. Lett.  2001,  6:  83 
• 6 Kabachnik MI. Medved TYa. Dokl. Akad. Nauk SSSR  1952,  689 ; Chem. Abstr. 1953, 47, 2724b
• 7 Gancarz R. Phosphorus, Sulfur Silicon Relat. Elem.  1993,  83:  59 
• 8 Gancarz R. Gancarz I. Walkowjak U. Phosphorus, Sulfur Silicon Relat. Elem.  1995,  104:  45 
• 9 Kabachnik MM. Ternovskaya TN. Zobnina EV. Beletskaya IP. Zh. Org. Khim.  2002,  38:  504 
• 10 Saidi MR. Azizi N. Synlett  2002,  1347 
• 11 Lidström P. Tierney J. Wathey B. Westman J. Tetrahedron  2001,  57:  9225 
• 12 Kabachnik MM. Zobnina EV. Beletskaya IP. Zh. Org. Khim.  2005,  41:  in press 
• 13a Mitra AK. De Karchaudhuri AN. Synlett  1998,  1345 
• 13b Yadav JS. Subba Reddy BV. Madan Ch. Synlett  2001,  1131 
• 13c Kaboudin B. Nazari R. Tetrahedron Lett.  2001,  42:  8211 
• 17 Bazloo M. Jiao X.-Y. Wojtowicz H. Rajan P. Verbruggen C. Augustyns K. Haemers A. Synthesis  1995,  1074 

14

General Procedure: a) Microwave irradiation: Appropriate ketone (IIIa-j, 0.02 mol), anhydrous amine (0.02 mol) and freshly distilled (EtO)₂P(O)H (0.06 mol) were placed into 25 mL flask and exposed to microwave irradiation at 102 W using a domestic oven (Daewoo, KOR-4125G) for 10-28 min. The residue was purified by chromatography on silica (eluent: hexane-EtOAc, 3:2).
All experiments were repeated several times in order to ensure reproducibility.
b) Conventional method: A mixture of ketone (0.05 mol), amine (0.05 mol) and diethyl phosphite was refluxed in benzene (20 mL) for an appropriate time. On completion, the solvent was evaporated and the residue was purified by chromatography on silica (eluent: hexane-EtOAc, 3:2).
All new compounds gave satisfactory elemental analyses (C ± 0.2, H ± 0.3, N ± 0.3).
¹H NMR, ³¹P NMR and microanalytical data for some newly obtained α-aminophosphonates are as follows.
Compound IIIc: bp 70-73 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.12 (t, ² J = 6.5 Hz, 6 H, CH₃CH₂O), 1.31 [s, 12 H, (CH₃)₂CH], 2.02 (m, 2 H, 2 ¥ (CH₃)₂CH), 2.91 (br s, 1 H, NH) 3.82 (q, J = 7.8, 6.3 Hz, 4 H, CH₃CH₂O), 3.97 (q, J = 7.1, 6.0 Hz, 2 H, CH₂-NH), 7.40 (m, 5 H, arom). ³¹P NMR (162 MHz, CDCl₃): δ = 26.1. Anal. Calcd for C₁₈H₃₂NPO₃: C, 63.34; H, 9.38; N, 4.11. Found: C, 63.15; H, 9.40; N, 4.13.
Compound IIId: bp 108-109 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.31 (t, ² J = 7.6 Hz, 6 H, OCH₂CH₃), 3.94 (dd, J = 7.6, 6.2 Hz, 2 H, NHCH₂), 4.08 (q, J = 7.1, 6.2 Hz, 4 H, 2 ¥ OCH₂CH₃), 4.16 (br s, 1 H, NH), 7.62, 7.49, 7.31 (m, 15 H, arom). ³¹P NMR (162 MHz, CDCl₃): δ = 28.0. Anal. Calcd for C₂₄H₂₈NPO₃: C, 70.13; H, 6.67; N, 3.21. Found: C, 70.41; H, 6.85; N, 3.42.
Compound IIIg: ¹H NMR (400 MHz, CDCl₃): δ = 1.40 (t, ² J = 7.6 Hz, 6 H, OCH₂CH₃), 1.7 (s, 3 H, CH₃), 2.24 (s, 3 H, CH₃), 3.63 (br s, 1 H, NH), 4.07 (q, J = 7.6, 5.2 Hz, 4 H, OCH₂CH₃), 4.09 (dd, J = 7.9, 6.4 Hz, 2 H, NHCH₂), 6.47 (d, J = 2.3 Hz, 1 H, thiophene), 6.56 (d, J = 3.4 Hz, 1 H, thiophene), 7.36 (m, 5 H, arom). ³¹P NMR (162 MHz, CDCl₃): δ = 24.8 ppm. Anal. Calcd for C₁₇H₂₆NSPO₃: C, 57.46; H, 7.32; N, 3.94. Found: C, 57.48; H, 7.53; N, 3.65.
Compound IIIh: ¹H NMR (400 MHz, CDCl₃): δ = 1.33 (t, J = 7.6 Hz, 6 H, OCH₂CH₃), 1.65 (d, J = 10.6 Hz, CH₃), 3.89 (br s, 1 H, NH), 3.94 (dd, J = 7.6, 5.9 Hz, 2 H, NHCH₂), 4.02 (q, J = 7.6, 5.2 Hz, 4 H, OCH₂CH₃), 7.62, 7.49, 7.31 (m, 12 H, arom). ³¹P NMR (162 MHz, CDCl₃): δ = 24.1 ppm. Anal. Calcd for C₂₃H₂₈NPO₃: C, 69.52; H, 7.05; N, 3.53. Found: C, 69.46; H, 7.34; N, 3.81.

15

To a solution of the ketone IV (0.001 mol) in ClCH₂CH₂Cl (1.5 mL), PhCH₂NH₂ (0.001 mol) and freshly distilled (EtO)₂P(O)H (0.003 mol) were added. The reaction mixture was exposed to microwave irradiation at 102 W using a domestic oven (Daewoo, KOR-4125G) for 24 min. The residue was purified by chromatography on silica (eluent: hexane-EtOAc, 3:2).
α-Aminophosphonate Derived from 3-Methoxy-androsta-3,5-diene-17-one (V): mp 143-145 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.92 (m, 1 H, 9-CH), 0.94 (s, 3 H, 18-CH₃), 1.04 (s, 3 H, 19-CH₃), 1.29 (t, J = 7.6 Hz, 6 H, OCH₂CH₃), 1.62 (m, 1 H, 8-CH), 1.82 (m, 14 H, all CH₂-ring), 2.25 (dd, J = 7.6, 5.9 Hz, 2 H, NHCH₂), 2.57 (br s, 1 H, NH), 3.61 (s, 3 H, CH₃O), 3.99 (q, J = 7.9, 5.4 Hz, 4 H, OCH₂CH₃), 5.39 (s, 1 H, 6-CH), 7.37 (m, 5 H, arom). ³¹P NMR (162 MHz, CDCl₃): δ = 23.0 and 26.0 ppm. MS (ESI⁺): m/z = 391.2 [C₃₁H₄₅NO₄P + H(EtO)₂P(O)].

16

To solution of ketone VI (0.048 mol) in ClCH₂CH₂Cl (1.5 mL), PhCH₂NH₂ (0.048 mol) and freshly distilled (EtO)₂P(O)H (0.144 mol) were added. The reaction mixture was exposed to microwave irradiation at 102 W using a domestic oven (Daewoo, KOR-4125G) for 4 min. The residue was purified by chromatography on silica (eluent: CH₂Cl₂-MeOH, 100:1).
α-Aminophosphonate Derived from 3,8-Diacetyl-13,17-bis(methoxycarbonylethyl)-2,7,12,18-tetramethyl-porphyrin (VII): ¹H NMR (400 MHz, CDCl₃): δ = 10.24, 9.99, 9.85, 9.84 (s, 4 H, meso-H), 4.34-4.28 (two over-lapping t, J = 7.4, 7.1 Hz, 4 H, 2 × CH₂CH₂CO₂CH₃), 4.22-4.12 [q, J = 7.1, 6.0 Hz, 8 H, 3¹-P(O)(OCH₂CH₃)₂], 4.16 (br s, 1 H, NH), 3.65, 3.65, 3.64, 3.57, 3.55, 3.52 (s, 18 H, 2 × CH₂CH₂CO₂CH₃ and 4 × CH₃-ring), 3.23-3.19 (two overlapping t, 4 H, 2 × CH₂CH₂CO₂CH₃), 1.68 (m, 2 H, 2 × CH), 1.30-1.26 [t, J = 7.1 Hz, 12 H, 3¹-P(O)(OCH₂CH₃)₂], 1.24 and 1.23 [s, 9 H, 3¹-NHC(CH₃)₃], -4.21 (br s, 2 H, 2 × NH-ring). ³¹P NMR (162 MHz, CDCl₃): δ = 19.5 ppm. MS (ESI⁺): 624.7 [C₅₂H₈₀N₆O₁₀P₂ + 2 H - 2 t-Bu -
2 (EtO)₂P(O)].

18

Cyclohexanone (0.02 mol), PhCH(CH₃)NH₂ (0.02 mol) and freshly distilled trimethylsilylphosphite (0.06 mol) were placed into 50 mL flask and exposed to microwave irradiation at 102 W using a domestic oven (Daewoo, KOR-4125G) for 18 min. The residue was purified by chromatography on silica (eluent: hexane-EtOAc, 3:2).
α-Aminophosphonic Acid VIII: bp 229 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.96 (d, J = 7.6 Hz, 3 H, CHCH ₃), 1.26 (m, 10 H, c-C₆H₁₀), 3.58 (s, 2 H, OH), 3.95 (q, J = 7.9, 6.4 Hz, 1 H, NHCH), 7.25 (m, 5 H, arom), 7.51 (br s, 1 H, NH). ³¹P NMR (162 MHz, CDCl₃): δ = 19.8 ppm. Anal. Calcd for C₁₄H₂₂NPO₃: C, 59.36; H 7.77; N, 4.95. Found: C, 59.08; H, 7.53; N, 5.02.