An Efficient One-Pot Synthesis of α-Amino Phosphonates Catalyzed by Bismuth Nitrate Pentahydrate

Abstract

A simple, efficient, and environmentally benign method has been developed for the synthesis of α-amino phosphonates through a one-pot reaction of aldehydes with amines and diethyl phosphite in the presence of bismuth nitrate pentahydrate as a catalyst. Some of the major advantages of this protocol are: good yields, the involvement of a less-expensive and non-toxic catalyst, mild and solvent-free reaction conditions and also tolerance towards other functional groups present in the substrates. Eighteen examples are described, highlighting the substrate scope of the reaction.

Key words

α-amino phosphonates - aldehydes - amines - alkyl phosphite - bismuth nitrate pentahydrate - synthetic methods

References and Notes

• 1a Giannousis PP. Bartlett PA. J. Med. Chem.  1987,  30:  1603 
• 1b Allen MC. Fuhrer W. Tuck B. Wade R. Wood JM. J. Med. Chem.  1989,  32:  1652 
• 2 Kafarski P. Leczak B. Phosphorus, Sulfur Silicon Relat. Elem.  1991,  63:  193 
• 3a Atherton FR. Hassall CH. Lambert RW. J. Med. Chem.  1986,  29:  29 
• 3b Allen JG. Atherton FR. Hall MJ. Hassall CH. Holmes SW. Lambert RW. Nisbet LJ. Ringrose PS. Nature (London)  1978,  272:  56 
• 3c Allen JG. Atherton FR. Hall MJ. Hassall CH. Lambert RW. Nisbet LJ. Ringrose PS. Antimicrob. Agents Chemother.  1979,  15:  684 
• 3d Atherton FR. Hall MJ. Hassall CH. Lambert RW. Ringrose PS. Antimicrob. Agents Chemother.  1979,  15:  677 
• 3e Atherton FR. Hall MJ. Hassall CH. Lambert RW. Lloyd WJ. Ringrose PS. Antimicrob. Agents Chemother.  1979,  15:  696 
• 4 Hassall CH. Hahn EF. Antibiotics   Vol VI:  Springer; Berlin: 1983.  p.1-11  
• 5a Hirschmann R. Smith AB. Taylor CM. Benkovic PA. Taylor SD. Yager KM. Sprengeler PA. Benkovic SJ. Science  1994,  265:  23 
• 5b Smith AB. Taylor CM. Benkovic SJ. Hirschmann R. Tetrahedron Lett.  1994,  35:  6856 
• 6a Petrov KA. Chauzov VA. Erokhina TS. Usp. Khim.  1974,  43:  2045 ; Chem. Abstr. 1975, 82, 43486
• 6b Kirby AJ. Warren SG. The Organic Chemistry of Phosphorus   Elsevier; Amsterdam: 1967. 
• 7 Laschat S. Kunz H. Synthesis  1992,  90 
• 8 Zon J. Pol. J. Chem.  1981,  55:  643 
• 9 Genet JP. Uziel J. Port M. Touzin AM. Roland S. Thorimbert S. Tanier S. Tetrahedron Lett.  1992,  33:  77 
• 10a Qian C. Huang T. J. Org. Chem.  1998,  63:  4125 
• 10b Lee S. Park JH. Kang J. Lee JK. Chem. Commun.  2001,  1698 
• 11 Ranu BC. Hajra A. Jana U. Org. Lett.  1999,  1:  1141 
• 12 Yadav JS. Reddy BVS. Raj KS. Reddy KB. Prasad AR. Synthesis  2001,  2277 
• 13 Chandrasekhar S. Prakash SJ. Jagadeshwar V. Narsihmulu C. Tetrahedron Lett.  2001,  42:  5561 
• 14 Komatsu N. Taniguchi A. Uda M. Suzuki H. Chem. Commun.  1996,  1847 
• 15 Eash KJ. Pulia MS. Wieland LC. Mohan RS. J. Org. Chem.  2000,  65:  8399 
• 16 Srivastava N. Banik BK. J. Org. Chem.  2003,  68:  2109 

17

Method A: To a mixture of aldehyde (1 mmol) and amine (1 mmol), BiNO₃·5H₂O (10 mol%) was added and stirred at r.t. for 5 min, then diethylphosphite (1 mmol) was added dropwise. The stirring of the reaction mixture was continued for the appropriate time (see Table [1] ) till the completion (TLC) of reaction. The reaction mixture was diluted with H₂O and extracted with EtOAc (3 × 20 mL). The combined EtOAc extract was washed with brine, dried (anhyd Na₂SO₄), and evaporated to furnish crude product, which was purified by column chromatography (hexane-EtOAc, 7:3) over silica gel to provide pure α-amino phosphonates. All the products were characterized by spectral data.
Method B: To a mixture of aldehyde (1 mmol), amine (1 mmol), and diethylphosphite (1 mmol), BiNO₃·5H₂O (10 mol%) was added and the reaction mixture was irradiated with microwave (Kenstar Model No. OM-9918C; 2450 MHz, 2350 W) for the specified period of time in an open vessel. Work-up of the reaction was carried out as described above.
Diethyl {[(2-Hydroxyphenyl)amino](phenyl)meth-yl}phosphonate ( 4h) Yield 0.304 g, 91%, colorless syrupy liquid. ¹H NMR (200 MHz, CDCl₃, TMS): δ = 7.46-6.46 (m, 9 H), 4.89 (d, ¹ J _PH = 26.0 Hz, 1 H), 3.61-4.33 (m, 4 H), 1.13 (t, J = 7.2 Hz, 3 H), 1.10 (t, J = 7.3 Hz, 3 H). ¹³C NMR (50 MHz, CDCl₃, TMS): δ = 145.29 (s, Ph), 135.73 (s, Ph), 134.88 (s, Ph), 128.56 (s, Ph), 128.51 (s, Ph), 128.18 (s, Ph), 128.07 (s, Ph), 127.85 (s, Ph), 119.88 (s, Ph), 118.25 (s, Ph), 114.38 (s, Ph), 111.94 (s, Ph), 64.31 (d, ² J _PC = 7.3 Hz, -OCH₂CH₃), 63.70 (d, ² J _PC = 7.0 Hz, -OCH₂CH₃), 55.99 (d, ¹ J _PC = 153.0 Hz, -CHP), 16.49 (d, ³ J _PC = 5.5 Hz, -OCH₂ CH₃), 16.19 (d, ³ J _PC = 5.9 Hz, -OCH₂ CH₃). Anal. Calcd for C₁₇H₂₂NO₄P (335.33): C, 60.89; H, 6.61; N, 4.18. Found: C, 60.72; H, 6.58; N, 4.10.
Diethyl [1,3-Benzodioxol-5-yl(phenylamino)meth-yl]phosphonate ( 4i)
Yield 0.355 g, 98%, white solid; mp 112-13 °C. ¹H NMR (200 MHz, CDCl₃, TMS): δ = 7.16-6.57 (m, 8 H), 5.94 (s, 2 H), 4.72 (d, ¹ J _PH = 23.1 Hz, 1 H), 4.17 (m, 4 H), 1.30 (t, J = 6.1 Hz, 3 H), 1.17 (t, J = 6.5 Hz, 3 H). ¹³C NMR (50 MHz, CDCl₃, TMS): δ = 145.29 (s, Ph), 144.80 (s, Ph), 144.51 (s, Ph), 143.92 (s, Ph), 143.85 (s, Ph), 127.35 (s, Ph), 125.49 (s, Ph), 125.44 (s, Ph), 119.21 (s, Ph), 116.59 (s, Ph), 112.12 (s, Ph), 108.67 (s, Ph), 108.58 (s, Ph), 61.64 (d, ² J _PC = 7.0 Hz, -OCH₂CH₃), 61.58 (d, ² J _PC = 7.1 Hz,
-OCH₂CH₃), 54.12 (s, -OCH₃), 53.91 (d, ¹ J _PC = 152.1 Hz, -CHP), 14.65 (d, ³ J _PC = 5.8 Hz, -OCH₂ CH₃), 14.47 (d, ³ J _PC = 6.0 Hz, -OCH₂ CH₃). Anal. Calcd for C₁₈H₂₂NO₅P (363.34): C, 59.50; H, 6.10; N, 3.85. Found: C, 59.32; H, 6.05; N, 3.78.

Diethyl [(4-Hydroxy-3-methoxyphenyl)(phenyl-amino)methyl]phosphonate ( 4k)
Yield 0.357 g, 98%, colorless syrupy liquid. ¹H NMR (200 MHz, CDCl₃, TMS,): δ = 7.14-6.60 (m, 8 H), 4.77 (d, ¹ J _PH = 24.4 Hz, 1 H), 4.16-3.67 (m, 4 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 1.28 (t, J = 7.43 Hz, 3 H), 1.10 (t, J = 7.2 Hz, 3 H). ¹³C NMR (50 MHz, CDCl₃, TMS,): δ = 145.34 (s, Ph), 145.29 (s, Ph), 144.80 (s, Ph), 143.85 (s, Ph), 127.35 (s, Ph), 125.44 (s, Ph), 119.21 (s, Ph), 116.59 (s, Ph), 112.84 (s, Ph), 112.12 (s, Ph), 108.67 (s, Ph), 108.58 (s, Ph), 63.44 (d, ² J _PC = 7.0 Hz, -OCH₂CH₃), 63.39 (d, ² J _PC = 7.3 Hz, -OCH₂CH₃), 54.12 (s, -OCH₃), 53.91 (d, ¹ J _PC = 152.0 Hz, -CHP), 16.48 (d, ³ J _PC = 6.4 Hz, -OCH₂ CH₃), 16.30 (d, ³ J _PC = 6.0 Hz,
-OCH₂ CH₃). Anal. Calcd for C₁₈H₂₄NO₅P (365.36): C, 59.17; H, 6.62; N, 3.83. Found: C, 59.05; H, 6.45; N, 3.78.
Diethyl [(2-hydroxy-6-methoxyphenyl)(phenyl-amino)methyl]phosphonate ( 4n)
Yield 0.346 g, 95%, white solid; mp 116-18 °C. ¹H NMR (200 MHz, CDCl₃, TMS,): δ = 7.13-6.64 (m, 8 H), 5.25 (d, ¹ J _PH = 24.2 Hz, 1 H), 4.21-3.86 (m, 4 H), 4.13 (s, 3 H), 1.29 (t, J = 7.0 Hz, 3 H), 1.10 (t, J = 7.0 Hz, 3 H). ¹³C NMR (50 MHz, CDCl₃, TMS): δ = 147.03 (s, Ph), 146.51 (s, Ph), 146.22 (s, Ph), 144.15 (s, Ph), 129.22 (s, Ph), 122.12 (s, Ph), 120.56 (s, Ph), 120.19 (s, Ph), 118.52 (s, Ph), 113.88 (s, Ph), 110.36 (s, Ph), 63.50 (d, ² J _PC = 7.2 Hz, -OCH₂CH₃), 56.07 (s, -OCH₃), 49.58 (d, ¹ J _PC = 155.6 Hz, -CHP), 16.50 (d, ³ J _PC = 6.1 Hz, -OCH₂ CH₃), 16.23 (d, ³ J _PC = 5.9 Hz, -OCH₂ CH₃). Anal. Calcd for C₁₈H₂₄NO₅P (365.36): C, 59.17; H, 6.62; N, 3.83. Found: C, 59.02; H, 6.42; N, 3.75.
Diethyl [(3-Hydroxy-4-methoxyphenyl)(phenyl-amino)methyl]phosphonate ( 4o) Yield 0.354 g, 97%, colorless syrupy liquid. ¹H NMR (200 MHz, CDCl₃, TMS,): δ = 7.12-6.57 (m, 8 H), 4.73 (d, ¹ J _PH = 24.0 Hz, 1 H), 4.15-3.68 (m, 4 H), 3.80 (s, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.12 (t, J = 7.0 Hz, 3 H). ¹³C NMR (50 MHz, CDCl₃, TMS,): δ = 147.02 (s, Ph), 147.00 (s, Ph), 146.37 (s, Ph), 129.19 (s, Ph), 128.59 (s, Ph), 119.60 (s, Ph), 118.37 (s, Ph), 118.18 (s, Ph), 114.67 (s, Ph), 114.01 (s, Ph), 63.55 (d, ² J _PC = 7.0 Hz, -OCH₂CH₃), 55.93 (s, -OCH₃), 55.51 (d, ¹ J _PC = 153.8 Hz, -CHP), 16.47 (d, ³ J _PC = 5.5 Hz, -OCH₂ CH₃), 16.30 (d, ³ J _PC = 5.8 Hz, -OCH₂ CH₃). Anal. Calcd for C₁₈H₂₄NO₅P (365.35): C, 59.17; H, 6.62; N, 3.83. Found: C, 59.12; H, 6.48; N, 3.78.
Diethyl {[4-(2,3-dihydroxypropoxy)phenyl](phenyl-amino)methyl}phosphonate ( 4r) Yield 0.392 g, 96%, colorless syrupy liquid. ¹H NMR (200 MHz, CDCl₃, TMS): δ = 7.39-6.57 (m, 9 H), 4.77 (d, ¹ J _PH = 25.6 Hz, 1 H), 4.14-3.65 (m, 4 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.13 (t, J = 7.3 Hz, 3 H). ¹³C NMR (50 MHz, CDCl₃, TMS): δ = 158.33 (s, Ph), 158.28 (s, Ph), 146.43 (s, Ph), 146.14 (s, Ph), 129.18 (s, Ph), 129.01 (s, Ph), 128.06 (s, Ph), 120.19 (s, Ph), 118.46 (s, Ph), 114.73 (s, Ph), 114.68 (s, Ph), 113.98 (s, Ph), 70.43 (s, -CHOH), 69.08 (s, -CH₂OH), 63.49 (d, ² J _PC = 7.3 Hz, -OCH₂CH₃), 63.43 (d, ² J _PC = 7.3 Hz, -OCH₂CH₃), 55.26 (d, ¹ J _PC = 151.0 Hz, -CHP), 16.42 (d, ³ J _PC = 5.5 Hz, -OCH₂ CH₃), 16.25 (d, ³ J _PC = 5.5 Hz,
-OCH₂ CH₃). Anal. Calcd for C₂₀H₂₈NO₆P (409.41): C, 58.67; H, 6.89; N, 3.42. Found: C, 58.50; H, 6.78; N, 3.36.