Some Aspects of Aminoalkylphosphonic Acids Synthesis by the

53 Some Aspects of Aminoalkylphosphonic Acids Synthesis by the Reductive Amination Approach P. S A V I G N A C Equipe CNRS-SNPE, 2-8 Rue Henry Dunant, 94320 Thiais, France

Downloaded by UNIV OF SYDNEY on July 25, 2013 | http://pubs.acs.org Publication Date: November 11, 1981 | doi: 10.1021/bk-1981-0171.ch053

N. COLLIGNON I.N.S.C.I.R., B.P. 08, 76130 Mont-Saint-Aignan, France

The discovery by Horiguchi and Kandatsu in 1960 of 2-aminoethy1phosphonic acid (ΑΕΡΑ) represents the first example of the occu rence of a covalent C-P bond in biological materials (1). Several laboratories attempted to elucidate the biosynthesis of the C-P bond. Horiguchi, who was studying the problem of ΑΕΡΑ induction, proposed two approaches (2) (Scheme 1). In the first, phosphonopyruvic acid (II) a substance produced by rearrangement of phosphoenolpyruvate (I) is readily decarboxylated to phosphonoacetaldehyde (III) and then via amination converted to ΑΕΡΑ. In the second, phosphonopyruvic acid (II) is at first transaminated to phosphonoalanine (IV) and then decarboxylated to ΑΕΡΑ. Recently Horiguchi has suggested that phosphonoalanine (IV) was deaminated in preference to decarboxylation (3). As seen in Scheme 1 a route similar to the biological pathway has now been explored by the inde pendent synthesis of each precur sors by chemical means. Work pre sented in this communication des cribes the production of synthetic 2-aminoethylphosphonic acids by the controlled reductive amination of 2-oxoalkylphosphonate diesters (Scheme 1) B r i e f l y we review the chemical improvements which we achieved i n the oxoalkylphosphonates f i e l d which represent the key com pounds . Phosphonic aldehydes are obtained i n adapting the Arbuzov procedure to $ or h a l o k e t a l s (4). A m o d i f i c a t i o n of the phosphon y l a t i o n c o n d i t i o n s (t°, stolchiometry) followed by removal of the p r o t e c t i n g group i n d i l u t e a c i d and then continuous e x t r a c t i o n allows synthesis of s u i t a b l y branched compounds on a large s c a l e (5). 0097-6156/81/017l-0255$05.00/0 © 1981 American Chemical Society

In Phosphorus Chemistry; Quin, L., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

256

PHOSPHORUS CHEMISTRY

1

R i BrCH (CH) CH(0R) 2

n

+

1

R ! * (RO) PCH (CH) CH(OR)

2

2

(RO)^P

2

I

n

1

H

+

2

R i ^ (RO) PCH (CH) CH0 2

2

n

0

Ο n-Buli

2

R -X η = 0,1 R

2

R

1

R

(R0) PCH(CH) CH(0R)2 It 0

R

1

» (RO) PCH(CH) CHO |l 0

2

2

n


2

n

Because of the Perkow r e a c t i o n , the above route f o r the pro d u c t i o n of ketophosphonates and phosphonopyruvates was abandoned. By c o u p l i n g α-copperalkylphosphonates w i t h a c y l c h l o r i d e s , we have been able to produce i n one step ketophosphonate c o r r e c t l y funct i o n a l i z e d as w e l l as phosphonopyruvates i n good y i e l d and high p u r i t y (6). l R

i' (R0) PCH 2

n-Buli Ϋ Cul f » (R0) PCHLi » (R0) PCHCu

2

2

^ ™ ^ ™ f 0 0

2

Il

II

«

0

0

0

C

£ K

°Φν

1 R (R0) PCHCC00R 2

II

0 R = Me,Et

R

1

= Η,Me,Εt

R

2

= alkyl,

aryl...

Phosphonopyruvate systems were the f i r s t candidates submit ted to r e d u c t i v e amination. Because of the presence of the e s t e r group, the α-ketoester carbonyl i s l e s s r e a c t i v e than t r a d i t i o n a l oxoalkylphosphonates, and y i e l d s of i s o l a t e d amino-esters never exceeded 55 %. The r e a c t i o n i s run at ρΗ 7 i n ethanol and i t i s general f o r ammonia and primary amines. S t e r i c hindrance repre sents the second l i m i t i n g f a c t o r s i n c e α-substituted or thionophosphonopyruvates r e a c t s l u g g i s h l y ; thus secondary amines cannot be introduced. When the r e d u c t i v e amination process i s e f f e c t e d the e x c l u s i v e by-product i s the α-hydroxyester which a r i s e s by r e d u c t i o n of the carbonyl group (7-8). D1 3

I X = 0,S

R1

D1

I NaBH CN,EtOH (RO)pPCHCCOOR m

I

H NR3 2

R

3

= H, Me, E t

| (RO) PCHCHC00R 2

II

1^3

H+

HO | m. >PCHCHC00H

HQ/11

I

H R 3

25 - 70 %

The amino-esters were hydrolyzed i n aqueous EC1 to give phosphonoalanine as a l a r g e v a r i e t y of d e r i v a t i v e s .


53.

SAViGNAC A N D COLLIGNON

Aminoalkylphosphonic Acids

257


Reductive amination was next c a r r i e d out w i t h the ketophosphonates. Our r e s u l t s i n d i c a t e that the s t e r i c hindrance around the carbonyl i s the l i m i t i n g f a c t o r . However the y i e l d s can be i n creased by i n c r e a s i n g the r e a c t i o n time without any side r e a c t i o n s lowering the p u r i t y of the products. Ammonia, primary and secondary amines can be introduced ; each one r e a c t s i n the enaminophosphonate form. Using ketophosphonate bearing f u n c t i o n a l groups we have observed e i t h e r a p a r t i c i p a t i o n of the f u n c t i o n a l group (halogen , ester or unsaturated group) to the r e a c t i o n or the complete conservation of the f u n c t i o n (aromatic group). The r e a c t i o n conduces a f t e r h y d r o l y s i s to a c i d s c o n t a i n i n g an asymétrie carbon. D1

D1

I NaBHjCN j (R0) PCHCR —(R0) PCHCHR H » tWK HNRκR ' "II3 k I . , 2

2

2

2

3

0

R

3

i+

0

0

h

= R = H, Me,

m

R

ο1 H+ HO j a» ^>PCHÇHR u Rι Q u ο NR 2

HQ

3

Et

55 - 80 %

The t h i r d type of compound studied were phosphonic aldehydes which are more r e a c t i v e . S t e r i c f a c t o r s are absent but we observe a d i f f e r e n c e i n behavior among phosphonicaldehydes according to the length of the carbon chain. Phosphonoacetaldehyde r e a c t s almost e x c l u s i v e l y i n the enaminophosphonate form which i s l e s s r e a c t i v e than the iminophosphonate form observed i n the case of homologous compounds. As f o r the aminating reagent we observe some d i f f e r e n ces. Ammonia always leads to a mixture of aminophosphonate ( i ) and aminodiphosphonate ( i i ) while primary and secondary amines lead s p e c i f i c a l l y to monocondensed compounds ( i ) (9). R

1 U

I 3

^(R0) P(CH) CH NR R 2

n

Lf

2

— •

Il

ϋ 1

I NaBH CN (R0) P(CH) CH0 »

R

A

1

I

H+

Np(CH) CH NR R m 110 3

n

i4

2

3

2

R

n

I η = 1,2

3

HNR R

R

i[R0)2|(tH) CH ]M

4

n

2

^ | o > | ( t H ) C H ] NH n

2

12

The above route f o r the production of primary aminophosphonic acids was abandoned f o l l o w i n g t h e i r s u c c e s s f u l s y n t h e s i s , i n good y i e l d and high p u r i t y , by the s u c c e s s i v e d e b e n z y l a t i o n (H /Pd/C)~ h y d r o l y s i s (aqueous HC1) of benzylaminoalkylphosphonate d i e s t e r s (10). 2

D1

D1

pi

j H NCH 0 f HO f (R0) P(CH) CHO ^ (R0) P(CH) CH=NCH 0 — * ^ P ( C H ) CH NH 2

2

2

2

Il 0

n

η = 1,2

II 0

2

n

2

HO^II 0

N

47 - 90 %


2

258

PHOSPHORUS

CHEMISTRY

In a d d i t i o n since the r e a c t i o n of 2-oxoethyl - phosphonate with amines showed a p r e f e r e n t i a l formation of an enaminophosphonate, we used that s t r u c t u r e f o r the production of s p e c i f i c a l l y nitrogen s u b s t i t u t e d compounds by the f o l l o w i n g sequence of reac tions (11). H NCH 0 2

2

(RO) PCH CHO 2

2

^ NaH (RO) PCH=CHNCH 0 « ^ 2

2

I

0

R

2

"

X

f (R0) PCH=CHNCH 0 2

2

0

H /Pd/C 2

HO ?


'

Me

>

E

t

'

P

r

35 - 55 %

H+

5 2CH NHR2 PCH

2

H

0

0 A l l the aminophosphonic acids prepared were obtained i n good y i e l d and p u r i f i e d by the use of i o n exchange r e s i n s (Amberlite IRA 410, 0ΗΓ form). Literature Cited

1. Horiguchi, M ; Kandatsu, M. Agr. Chem. Soc. Japan. 1960,24,565 2. Horiguchi, M ; Kittredge, J.S ; Roberts, E. Biochim .Biophys Acta 1968,165,164 3. Horigane, A ; Horiguchi, M ; Matsumoto, Τ ; ibid. 1979,572,385 4. Razumov, A.I ; Liorber, B.G ; Moskva, V.V ; Sokolov, M.P Russ. Chem. Rev. 1973,42,538 5. Varlet, J.M ; Fabre, G ; Sauveur, F ; Collignon, Ν ; Savignac, Ρ Tetrahedron (in preparation) 6. Mathey, F ; Savignac, Ρ ; Tetrahedron 1978,34,649 7. Borch, R.F ; Bernstein, M.D ; Durst H.D.J. Am. Chem. Soc 1971, 93, 2897 8. Varlet, J.M ; Collignon, Ν ; Savignac, Ρ ; Can . J . Chem 1979, .57, 3216 9. Isbell, A.F ; Englert, L.F ; Rosemberg, H ; J. Org. Chem 1969, 34, 755 10. Szczepaniak, W ; Kuczynski, Κ ; Phosphorus and Sulfur 1979,7, 333 11. Nagata, W ; Hayase, Y ; J. Chem. Soc (c), 1969, 460 RECEIVED

July 7, 1981.


Some Aspects of Aminoalkylphosphonic Acids Synthesis by the

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