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Organophosphorus Compounds of Expected Biological Activity, Part II* Preparation of Thiourea Derivatives and N-Aryl-phosphorothiomonoamidates

F . I . A b d e l - H a y , M . A . O m a r a , A . A . E l - B a r b a r y , a n d M . E l - B a d a w i

C h e m i s t r y D e p a r t m e n t , F a c u l t y o f S c i e n c e , T a n t a U n i v e r s i t y , T a n t a , A . R . E .

Z . N a t u r f o r s c h . 8 4 b , 2 9 7 - 2 9 9 ( 1 9 7 9 ) ; r e c e i v e d O c t o b e r 1 6 , 1 9 7 8

O r g a n o p h o s p h o r u s C o m p o u n d s , T h i o u r e a D e r i v a t i v e s , B i o l o g i c a l A c t i v i t y

T h e e x a m p l e s o f c y c l o d i p h o s p h a z a n e s s o f a r s t u d i e d d o n o t c o n t a i n a n y n u c l e i o f b i o l o g i c a l i n t e r e s t [ 1 ] . I n t h e p r e s e n t i n v e s t i g a t i o n w e a i m e d t o i n t r o d u c e e t h y l p - a m i n o -b e n z o a t e , 2 - a m i n o p y r i d i n e r e s i d u e s i n t h e p h o s p h a z a n e m o l e c u l e . F o r t h i s p u r p o s e p h o s -p h o r u s p e n t a c h l o r i d e w a s t r e a t e d w i t h e t h y l p - a m i n o b e n z o a t e , p - a n i s i d i n e , 2 - a m i n o -p y r i d i n e a n d 5 - a m i n o q u i n o l i n e t o g i v e l , 3 - d i - j 9 - e t h o x y c a r b o n y l p h e n y l - , l , 3 - d i - j 9 - m e t h o x y -p h e n y l - , l , 3 - d i - 2 - p y r i d y l - a n d l , 3 - d i - 5 - q u i n o l i n y l - 2 , 2 , 2 , 4 , 4 , 4 - h e x a c h l o r o c y c l o - d i p h o s -p h a z a n e (la-d), r e s p e c t i v e l y . T h e c o m p o u n d s la-d w e r e t r e a t e d w i t h p o t a s s i u m t h i o -c y a n a t e i n a c e t o n e . T h e o i l y p r o d u c t s f o r m e d w e r e t h e n t r e a t e d w i t h p - a n i s i d i n e , e t h y l - p -a m i n o b e n z o a t e a n d 2 - a m i n o p y r i d i n e w h e r e u p o n s o l i d p r o d u c t s (2a-h) w e r e o b t a i n e d . T h e r e a c t i o n p r o b a b l y t a k e s p l a c e a c c o r d i n g t o t h e f o l l o w i n g m e c h a n i s m [2].

la: b: c: d:

Ar

1 A r

C2H 5 O O C C 6 H4 - ( p ) C H 3 O C 6 H 4 - ( p ) C 5 H 4 N - ( 2 ) C 9 H 6 N - ( 5 )

Ar

Cl / N Cl c i > 0 < c i SCN NCS

2a: b: c: d: e: f: g: h:

A r

C2H500CC6H4-(?)) C2H5OOCC6H4-(jo) C2H5OOCC6H4-(2>) C 5 H 4 N - ( 2 ) C 5 H 4 N - ( 2 ) C H 3 O C 6 H 4 - ( / ) ) C H 3 O C 6 H 4 - ( p ) C H 3 0 C 6 H 4 - ( P )

A r '

Ring cleavage

N-Ar II Cl-lj'-Cl

NCS I Ar'NH

N-Ar II Ar NH-Fj'-NHAr

HN-C-NHAr' II S

2

C H 3 O C 6 H 4 - ( j 9 ) C 2 H 5 O O C C 6 H 4 - ( p ) C 5 H 4 N - ( 2 ) C H 3 O C 6 H 4 - ( p ) C2H5OOCC6H4-(jo) CH3OC6H4-(?)) C2H5OOCC6H4-(i9) C 5 H 4 N - ( 2 )

The structure of 2 was inferred from: 1. Their analytical data. 2. Their infrared absorption spectra which showed

bands at 3320-3125 cm-1, 1340-1335,1290-1265, 1202-1170 cm-1 characteristic of vN-H, vC=S, vP=N and vP-N respectively [3] (Table I).

* P a r t I s u b m i t t e d f o r p u b l i c a t i o n i n R e v u e R o u m a i n e d e C h i m i e 1 9 7 8 .

R e q u e s t s f o r r e p r i n t s s h o u l d b e s e n t t o D r . A . A . E l b a r b a r y , C h e m i s t r y D e p a r t m e n t , F a c u l t y o f S c i e n c e , T a n t a U n i v e r s i t y , Tanta, E g y p t . 0 3 4 0 - 5 0 8 7 / 7 9 / 0 2 0 0 - 0 2 9 7 / $ 0 1 . 0 0 / 0

T a b l e I . T h e i n f r a r e d s p e c t r a o f l , 2 , 2 - t r i a r y l - 2 - ( N -a r y l t h i o u r e a ) m o n o p h o s p h a z e n e s (2).

C o m -p o u n d

v N - H [ c m - 1 ]

*>P = N i > P - N vC = S vC=0

2 a 3 1 8 0 1 2 9 0 1 1 7 5 1 3 4 0 1 7 0 0 2 b 3 1 9 0 1 2 7 0 1 2 0 2 1 3 3 8 1 7 2 0 2c 3 1 2 5 1 2 6 5 1 1 9 0 1 3 3 0 1 7 1 2 2d 3 1 8 0 1 2 6 5 1 1 9 0 1 3 3 8 1 7 0 0 2c 3 1 8 0 1 2 8 0 1 2 0 0 1 3 3 8 1 7 1 5 2f 3 1 7 0 1 2 9 0 1 1 7 4 1 3 3 8 —

2 g 3 3 2 0 1 2 7 0 1 1 9 0 1 3 3 5 1 7 0 5 2h 3 1 7 0 1 2 9 0 1 1 7 0 1 3 3 5 —

The benzocaine moeity [4] was also confirmed by the presence of the carbonyl band at 1725 to 1700 cm-1 in the IR spectra of 2a-g (Table I). Their electronic spectra which showed great similarity to each other indicating that they contain nearly identical chromophores (Table II).

T a b l e I I . T h e e l e c t r o n i c s p e c t r a o f 2.

C o m - ^max £max ^max £max ^max £max p o u n d [ n m ] [ n m ] [ n m ]

2b 223.5 89675 268.5 27250 2d 216.5 48200 227 s h 43130 274 40100 2f 214.5 69320 2 3 5 s h 53290 273.5 60900 2h 213.5 39375 2 3 5 s h 29750 274 33833

s h — s h o u d l e r .

Moreover, the reaction of cyclodiphosphazanes (1) with thiophenol and 2-mercaptobenzothiazole was investigated. Thus the cyclodiphosphazanes (la-d) were treated with thiophenol and 2-mercaptobenzo-thiazole in the presence of pyridine. The reaction was found to occur in a similar manner to that of phenol [2],

298 F. I. Abdel-Hay et al. • Organophosphorous Compounds of Expected Biological Activity

Ar

CL I Ct

Ar 1

Ar' SH Cl

Ar'S> Ar'S-Ar'S'

• SAr' P ^ - S A r '

\sAr' -Ar'SAr'

S* Ar'S'

Ar

"U I I SAr'

Ar

S

SAr' Ar"

SAr |

Ar'S'

S P—SAr'

NH I , I SAr

Ar

NHAr , I

Ar S-P=S I SAr'

Ar I

,N c

Ar ®SAr' SAr'

e I Ar-N-P=S

I SAr1

I"' . SAr I

Ar -NH-P=S SAr'

A r A r '

8 a : C 2 H 5 O O C C 6 H 4 - ( p ) C 6 H 5 -b : C H 3 O C 6 H 4 - ( p ) c : C H 3 O C 6 H 4 - ( j o ) d : C 5 H 4 N - ( 2 ) e : 2 - b e n z o t h i a z o l y l ! : C 9 H 6 N - ( 5 )

C6H5-2 - b e n z o t h i a z o l y l C6H5-C 5 H 4 N - ( 2 ) C6H5-

The structure of 3 is inferred from:

i) Their analytical data.

ii) The infrared spectra of compounds 3e and 3f which showed bands characteristic for their functional groups [5] (Table III).

T a b l e I I I . T h e i n f r a r e d s p e c t r a o f 3 e a n d 3 ! .

C o m p o u n d N - H [ c m - 1 ] P - N [ c m - 1 ] P = S [ c m - 1 ]

3 e 3 1 1 0 1 1 2 5 1 0 9 0

3 ! 3 1 6 0 1 1 8 0 1 1 1 5

iii) Their electronic spectra which showed close similarity, indicating that they contain nearly similar chromophores (Table IV).

T a b l e I V . T h e e l e c t r o n i c s p e c t r a o f 3 .

C o m p o u n d Amax [ n m ] £max Amax [ n m ] £max

3 a 2 1 0 7 2 6 8 0 2 3 0 . 5 7 1 9 4 0

3 b 2 1 2 3 3 3 9 5 2 3 3 3 1 9 4 0

3 c 2 2 4 4 4 2 3 2 2 3 6 3 0 1 5 8 2 7 5 2 3 5 5 0 3 1 6 1 7 2 3 3

3 d 2 1 1 3 0 6 0 0 2 3 0 2 6 6 3 3

3 e 2 0 6 . 5 2 7 9 5 6 2 3 7 4 7 1 7 6 3 1 7 6 1 7 3 7

3 ! 2 2 2 2 9 5 2 8 2 7 8 4 0 3 8 0

The ring cleavage and rearrangement from 1 to 2 and 3 is indicated by the disappearance of the n-71* band characteristic of four-membered rings [6] in the spectra of 2b and 3a, b, d, e. However, the band within 270-278 nm in spectra of other com-pounds corresponds to the middle-energy band (xLb) of the aromatic ring.

Experimental Biological Activity

The above compounds were screened against various types of bacteria using a modified cup-test assay technique [7, 8]. The data revealed that the majority of them showed activity against Bacillus subtilis, Escherichia coli, Candida albicans and Sarcina lutea.

All melting points are not corrected. Micro-analyses were carried out by Micro-Analytical Lab., N. R. C., Cairo, Egypt. The UV spectra were measured in ethanolic solution using Unicam SP 8000 Ultraviolet Recording Spectrophotometer.

Preparation of 1,2,2-triaryl-2-N-arylthioureamono-phosphazenes

General procedure: To a solution of 1,3-diaryl-2,2,2,4,4,4-hexachlorocyclodiphosphazane (001 mole) in dry acetone (100 ml) at 0 °C was added dropwise with continuous stirring a solution of potassium thiocyanate (0.06 mole). The reaction mixture was then refluxed for few minutes and the precipitated potassium chloride was filtered. The filterate was treated with a primary amine (0.06 mole) in dry acetone (100 ml) at 0 °C under anhydrous conditions. The reaction mixture was stirred for one hour, and the solvent was removed by distillation under vacuum and on cooling a white solid separated out.

The solids so obtained were crystallised from the suitable solvent (Table V).

Reaction of 1,3-diaryl-2,2,2,4,4,4-hexachlorocyclo-diphosphazanes with thiophenol and 2-mercaptobenzo-thiazole

General procedure: To a solution of 1,3-diaryl-2,2,2,4,4,4-hexachlorocyclodiphosphazane (0.01 mole) in dry benzene (150 ml) containing 5 ml of dry pyridine was added with stirring (0.09 mole) of thiophenol or 2-mercaptobenzothiazole in dry benzene (100 ml). The reaction mixture was refluxed under anhydrous conditions for 6 h, then kept overnight at room temperature. The formed pyridine hydrochloride was filtered off and the filtrate was evaporated under vacuum. The residue was washed with ethanol to remove the unreacted thiophenol or mercaptobenzothiazole. The remaining solid was crystallised from the suitable solvent to 3 (Table VI).

F. I. Abdel-Hay et al. • Organophosphorus Compounds of Expected Biological Activity 299

Compound m.p. [°C] Yield Formula Analysis [ % ] Calcd (Found) Compound (solvent) [%] C H N P S

2a 190 65 C 3 I H 3 4 N 5 0 5 P S 60.09 5.49 11.31 5.01 5.17 (A) (59.81) (5.22) (11.20) (4.82) (4.81)

2b 168 63 C37H4ON508PS 59.60 5.37 9.40 4.16 4.30 (A) (59.94) (5.48) (9.21) (3.81) (3.93)

2c 175 62 C25H25N8OOPS 56.39 4.70 21.05 5.83 6.02 (B) (56.81) (4.41) (20.81) (4.50) (6.00)

2d 195 69 C27H29N603PS 59.42 5.29 - 5.66 5.84 (A) (58.74) (5.04) - (5.20) (6.21)

2e 169 70 C33H35N6O6PS 58.75 5.19 12.46 4.60 4.75 (A) (58.60) (4.91) (12.19) (3.95) (3.41)

2f 199 60 C 2 9 H 3 2 N 5 0 4 P S 60.31 5.55 12.13 5.37 5.54 (C) (60.00) (5.31) (11.91) (5.01) (5.22)

2g 173 70 C35H38N5O7PS 59.74 5.41 9.96 4.41 4.55 2g (A) (59.54) (5.22) (10.01) (4.21) (4.31)

2h 198 65 C23H23N8OPS 56.33 4.69 22.86 6.23 -

(A) (56.21) (4.42) (22.37) (6.01) -

Table V. 1,2,2-Tri-aryl - 2 -N-arylthiourea-monophosphazenes (2).

A = ethanol, B = methanol, C — benzene.

Compound m.p. [°C] (solvent)

Yield [ % ] Formula Analysis [ % ] Calcd (Found) C H N P S

3a 82 70 C 2 I H 2 0 N O 2 P S 3 56.63 4.49 3.15 6.97 21.57 (B) (56.55) (4.37) (2.95) (7.62) (21.43)

3b 115 66 C19H18NOPS3 56.58 4.47 7.79 23.82 (B) (56.21) (3.98) (7.21) (24.01)

3c 188 60 C 2 I H I 6 N 3 0 P S 5 49.74 3.09 8.12 6.00 30.95 (A) (49.13) (3.01) (7.00) (5.80) (29.80)

3d 110 65 C I 7 H I 5 N 2 P S 3 54.55 4.01 7.49 25.67 (C) (54.21) (3.08) (7.20) (24.91)

3e 180 55 C I 9 H I 3 N 4 P S 5 46.72 2.66 11.48 6.35 32.79 (B) (46.49) (2.49) (11.30) (6.21) (33.01)

3 ! 107 59 C 2 I H 1 7 N 2 P S 3 59.43 4.01 6.60 7.31 22.64 (B) (58.92) (4.20) (6.91) (7.69) (23.17)

Table VI. Compound 3.

A = ethanol, B = methanol, C = petroleum ether

b.p. 60-80 °C.

[1] A. C. Chapmann, N. L. Paddock, and H. T. Searle, J. Chem. Soc. 1961, 1825.

[2] I. Salama, M. Sc. Thesis, Al-Azhar University, Faculty of Science, Cairo 1974.

[3] A. M. Islam, E. A. Hassan, E. H. Ibrahim, and A. E. Arifien, Egypt. J. Chem. 17, 561 (1974).

[4] A. S. V. Burgen and J. F. Michel, Gaddum's Pharmacology, Oxford sixth ed., p. 47, Oxford 1969.

[5] Bellamy, The Infrared Spectra of Complex Molecules, Metheun, London 1966.

[6] S. Trippett, J. Chem. Soc. 1962, 4731. [7] T. Yamagushi, T. Kashida, K. Netwa, T. Yajma,

T. Miyagishima, Y . Ito, and T. Okuda, J. Anti-biotics 23, 373 (1970).

[8] A. A. Abou-Zeid, M. M. Abdel-Hamid, and Y . M. Shehata, Z. Allg. Microbiol 16, 337 (1976).