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Synthetic Communications: AnInternational Journal for RapidCommunication of SyntheticOrganic ChemistryPublication details, including instructions forauthors and subscription information:http://www.tandfonline.com/loi/lsyc20

Synthesis of β-AminoPhosphonates in One-PotProcedureWon Bum Jang a , Won Suk Shin a , Kilsung Lee a &Dong Young Oh aa Department of Chemistry , Korea AdvancedInstitute of Science and Technology , 373-1, Kusung-Dong, Yusung-Gu, Taejon, 305-701, Korea E-mail:Published online: 22 Aug 2006.

To cite this article: Won Bum Jang , Won Suk Shin , Kilsung Lee & Dong YoungOh (1997) Synthesis of β-Amino Phosphonates in One-Pot Procedure, SyntheticCommunications: An International Journal for Rapid Communication of SyntheticOrganic Chemistry, 27:23, 4101-4105, DOI: 10.1080/00397919708005457

To link to this article: http://dx.doi.org/10.1080/00397919708005457

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SYNTHETIC COMMUNICATIONS, 27(23), 4101-4105 (1997)

Synthesis of P-Amino Phosphonates in One-Pot Procedure

Won Bum Jang, Won Suk Shin,

Kilsung Lee and Dong Young Oh*

Department of Chemistry, Korea Advanced Institute of Science and Technology, 373- I , Kusung-Dong, Yusung-Gu, Taejon, 305-701, Korea

e-mail address : dyoh0,sorak.kaist.ac.h

Abstract : p -amino phosphonate derivatives are synthesized in one-pot procedure via reduction of p -enamino phosphonate intermediates with NaBHdacetic acid or trijluoroacetic acid.

The phosphonic acids and their esters, which are more resistant to hydrolysis than phosphates, could find wide application in biochemistry as regulators for

metabolic processes. I In this area, aminoalkanephosphonic acids as analogues of

natural aminocarboxylic acids occupy an important place. In 1959, Horiguchi and

Kandatsu2 first described the isolation of 2- aminoethylphosphonic acid (2-AEP)

from ciliate protozoa. Since then, 2-AEP has been found in numorous other

organisms and a new area of biochemistry has grown up around this compounds.

A review covering development through March 1964 is available. 2-AEP was first

synthesized by Finkelstein4 by the use of the Hoffman reaction. After that, several

synthetic methods for 2-aminoethylphosphonic acid and its analogues have been

de~eloped.~ From our synthetic work on p-enamino phosphonates,6 we seport here

more convenient, one-pot procedure for a synthesis of p-amino phosphonates.

4101

Copyright 0 1997 by Marcel Dekker, Inc.

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4102 JANG ET AL.

Our first trial for the synthesis of P-aminophosphonates using lithiated

methylphosphonate and intermediate 1 from nitrile and DIBAL-H gave only unexpected benzylidenebenzylamine 3 (Scheme 1). This result shows that 1 might not be enough electrophilic to the lithiated methylphosphonate, and readily

dimenzed'.

And we carried out reduction of the enamine intermediate 46, which could be

obtained from reaction of lithiated methylphosphonate and nitrile (Scheme 2). As a result, some products were prepared as shown Table. We obtained better result using acetic acid rather than trifluoroacetic acid (entry 1, 2 in Table). Satisfying result was obtained when sufficient reducing time is given (entry 3, 4 in Table). But, when alkylphosphonate, except methylphosphonate, was used, no reduced product was obtained. This is a limit of this reaction.

Scheme 2

Experimental

General Procedure for the Preparation of P-Aminophosphonates

To a stirred solution of diethyl methylphosphonate (1 mmol) in dry THF (3 ml),

is added BuLi (1 mmol, 1.6 M in hexane) at -78 OC under Nz atmosphere. After

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P-AMINO PHOSPHONATES 4103

being stirred for lh at the same temperature, nitrile (1 mmol) is added and the

mixture is warmed to -5 O C for lh. NaBH4 (2 mmol) and CH3COOH (or

CF3COOH) are added and the mixture is warmed to r.t. After maintain at r.t for 15h, 3% HCl(3 ml) is added and stirring continued for lh. The mixture is washed with ether (2 x 5ml). The mixture is made alkaline @H 12) with NaOH pellets and then extracted with EtOAc (3 x 20 ml). The combined organic extracts are dried

(MgSO4) and evaporated to give P-aminophosphonate.

Table. Synthesis of P-Aminophosphonates

Nitriles Proton Sources Reduction Time (hr) Y ields(%)a

PhCN

C H 3 o C N

PhCN

PhCN

t-

CF3COOH 2.5 56

2.5 R

CH3COOH 2.5 89

15 88

15 83

15 85

24 65

~

a. Isolation Yield.

Diethyl (2-amino-2-pheny1)ethylphosphonate

'H NMR : (200 MHz, cDcl3) 6 1.29 (t, J 7.0 Hz, 6H), 2.00-2.20 (m, 4H),

4.07 (9, J = 7.1 Hz, 4H), 4.40 (m, IH), 7.20 - 7.42 (m, 5H); I3C NMR : (50

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4104 JANG ET AL.

MHz,CDCI3) 6 16.00 ( d , J = 6.1 Hz), 35.78 (d, J = 135.9 Hz), 50.82, 50.90,

61.32 (dd, J = 3.3 and 6.5 Hz), 125.79, 126.61, 127.04, 128.13, 128.24,

145.08, 145.39; 31P NMR (120 MHz, CDC13) 6 29.818; IR 3295-3365 (VNH~) ,

1235 (vpz0); HRMS @I) calc. 257.1 181, obs. 257.1 170.

Diethyl (2-amino-2-(4-methylphenyl))ethylphosphonate

'H NMR : (200 MHz, CDC13) 6 1.30 (t, J = 7.0 Hz, 6H), 2.00-2.20 (m, 4H),

2.32(s, 3H), 4.08 (q, J = 7.1 Hz, 4H), 4.38 (m, IH), 7.13(d, 8.0 Hz, 2H),

7.27(d, 8.0 Hz, 2H); 13C NMR : (50 MHz, CDCl3) 6 16.02, 16.14, 20.69, 35.84

(d, J = 135.6 Hz), 50.53, 50.61, 61.18, 61.25, 61.31, 61.38, 125.69, 126.52,

128.83, 128.90, 136.63, 142.19, 142.50; IR 3290-3365 (vNHz), 1230 ( v ~ = ~ ) .

Diethyl (2-amino-2-(4-chlorophenyl))ethylphosphonate

'H NMR : (200 MHz, CDC13) 6 1.30 (t, J = 7.0 Hz, 6H), 2.03-2.27 (m, 4H),

4.07 (q, J = 7.3 Hz, 4H), 4.39 (m, lH), 7.24 - 7.39 (m, 4H); 13C NMR : (SO

MHz, CDCl3) 6 15.98, 16.10, 35.60 (d, J = 136.4 Hz), 50.26, 50.33, 61.30,

61.44, 127.34, 128.29, 132.61, 143.40, 143.72; IR 3290-3370 (vNHJ, 1230

(VP=O).

Diethyl (2-amino-3-methy1)butylphosphonate

'HNMR : (200 MHz, CDCl3) 6 0.91(dd, J = 2.6 and 6.8 Hz, 6H), 1.34 (t, J =

7.0 Hz, 6H), 1.50 - 2.20 (m, SH), 3.04 (m, lH), 3.95-4.20 (m, 4H); IR 3320-

3385 ( v m ) , 1230 (vp=o).

Acknowledgement : This paper was supported by NON DIRECT RESEARCH FUND, Korea Research Foundation

References

I . R. Engel, Chem. Rev., 1977, 77, 349.

2. M. Horiguchi and M. Kandatsu, Nature (London), 1959, 184, 901.

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[3-AMINO PHOSPHONATES 4105

3. L. D. Quin, 'Topics in Phosphorus Chemistry' vol. 4, M. Grayson and E. J. Griffith, Ed., Interscience, N. Y., P 23, 1966.

4. J. Finkelstein, J. Am. Chem. SOC., 1946, 68, 2397,.

5. (a) A. F. Isbell, J.P. Beii-y, L. W. Tansey, J. Org. Chem., 1972, 37, 4399. (b) J. Bai-ycki, P. Mastalerz, M. Soroka, Tetraherlron Lett., 1970, 3147. (c) P. Savignac, Synth. Cominirn., 1978, 8, 335. (d) G. Fabre, N.

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6. (a) K. Lee, D. Y. Oh, Syrtthesis,l991, 213. (b) K. Lee, W. S. Shin, D . Y. Oh, Synthetic Commun., 1991,21, 1657. (c) K. Lee. D. Y. Oh, Bull .

Kor. Chem. Soc., 1991, 12, 254. (d) W. S. Shin, K. Lee, D. Y. Oh,

Tetrahedron Lett., 1995,36, 281.

7 . In the case of reducing the aromatic nitrile with DIBAL-H or catalytic hydrogenation, benzylidenebenzylamine was produced as a minor product (Benzaldehyde was produced as a major product.): (a) A. E. G. Miller, J. W. Biss, L. H. Schwartzman, J. Org. Chem., 1959, 24, 627. (b) R. Juday, H. Adkins, J. Am. Chem. SOC., 1955, 77, 4559.

(Received i n Japan 31 March 1997)

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