studies on organophosphorus compounds: synthesis and reactions of...

Heteroatom ChemistryVolume 19, Number 5, 2008

Studies on Organophosphorus Compounds:Synthesis and Reactions of [1,2,4,3]Triaza-phospholo[4,5-a]Quinoxaline DerivativeHassan M. Moustafa and Mounir A. A. MohamedChemistry Department, Faculty of Science, Sohag University, Sohag, Egypt

Received 12 May 2007; revised 7 December 2007, 8 March 2008

ABSTRACT: 2,4-Bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson’sreagent) (1) reacted with 2-hydrazino-3-methyl-quinoxaline (2) to give [1,2,4,3]-triazaphospholo[4,5-a]quinoxaline derivative 3. The Mannich reactionusing different amines on compound 3 gave Mannichbases 4a–d. Also, compound 3 reacted with formalde-hyde to give the corresponding 2-hydroxymethylderivative 5, which upon reaction with thionyl chlo-ride gave the corresponding chloromethyl derivative 6.Treatment of compound 6 with some thiols yielded thecorresponding sulfides 7a–d. Acylation of compound3 gave acylated compounds 8a,b. Compound 9,which was prepared through the reaction of com-pound 3 with ethyl cyanoacetate, was investigatedas a starting material for the synthesis of somenew heterocyclic systems 10–13. Also, reaction ofcompound 9 with carbon disulfide and 2 equivalentsof methyl iodide in a one-pot reaction yielded thecorresponding ketene-S,S-acetal 14, which in turnreacted with bidentates to give some new heterocycles15–17. C© 2008 Wiley Periodicals, Inc. Heteroatom Chem19:520–529, 2008; Published online in Wiley InterScience(www.interscience.wiley.com). DOI 10.1002/hc.20473

Correspondence to: Hassan M. Moustafa; e-mail:[email protected]© 2008 Wiley Periodicals, Inc.

INTRODUCTION

Quinoxalines have been found to be biologicallyactive compounds having antiviral [1], antimi-crobial [2], and anticancer [3] properties. Also,organophosphorus compounds possess a large va-riety of interesting pharmacological and biologicalactivities that include herbicidal [4], insecticidal[5,6], antibacterial [7,8], antifungal [7,9], andanticancer [10] properties. In view of the aboveobservations and in continuation of our studies inthe same area [11–14], it was of interest to fuseP-heterocycles with the quinoxaline nucleus, withthe hope that the newly synthesized compoundsmight exhibit enhanced biological properties. 2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson’s reagent, LR, 1) has beenshown to be quite versatile in thiation of differentcarbonyl compounds [15–17], and it is also knownthat nucleophiles attack compound 1 at the phos-phorus atom. In certain cases, where the substratecontains two functional groups or can react in dif-ferent ways, P-heterocycles are formed [18–22]. Asan extension of our general studies on the reagent 1,its reaction with quinoxaline derivatives is reportedin this work.

RESULTS AND DISCUSSION

2-Hydrazino-3-methylquinoxaline (2) [23,24] wasprepared in good yields by the reaction of thecorresponding methyl sulfone with hydrazine hy-drate. Compound 2 was allowed to react with LR (1)

520

Synthesis and Reactions of [1,2,4,3]Triaza-phospholo[4,5-a]Quinoxaline Derivative 521

SCHEME 1

in boiling acetonitrile to give 1-(4-methoxyphenyl)-4-methyl-1,2-dihydro-[1,2,4,3]-triazaphospholo[4,5-a]quinoxaline-1-sulfide (3). It was suggested thatthe amino group of the hydrazone attacks LRgiving the intermediate A followed by ring closurethrough elimination of H2S to give compound 3(cf. Scheme 1)

The structure of compound 3 was confirmedon the basis of its elemental and spectral analysis(cf. Table 1).

The IR spectrum of compound 3 showed the ab-sence of the absorption bands corresponding to theNH2 group while exhibiting characteristic bands cor-responding to P S at 652 cm−1. The 1H NMR spec-trum of compound 3 showed the absence of the sig-nal corresponding to the NH2 group while exhibitinga signal corresponding to three aliphatic protons at3.9 ( OCH3, s).

The Mannich reaction on compound 3 usingformaldehyde and different amines namely ben-zylamine, aniline, morpholine, and diethylamineafforded the corresponding Mannich bases 4a–d(cf. Scheme 2). The IR and 1H NMR spectra ofthese compounds confirm their proposed structures(cf. Table 1).

Also, compound 3 reacted with formaldehyde togive the corresponding 1-hydroxymethyl derivative5, which in turn reacted with thionyl chloride togive the corresponding 1-chloromethyl derivative 6.Treatment of compound 6 with aliphatic, aromatic,or heterocyclic thiols acting as a sulfur nucleophile

in boiling ethanol in the presence of sodium ethox-ide yielded the corresponding sulfides 7a–d in goodyields (cf. Scheme 2).

Acetylation and benzoylation of compound3 gave N-acylated compounds 8a,b, respectively(cf. Scheme 2).

The reaction of compound 3 with ethyl cyanoac-etate in the presence of sodium t-butoxide affordedN-cyanoethyl derivative 9. Refluxing of compound 9with LR (1) in toluene gave the corresponding thio-compound 10. Treatment of compound 10 with ben-zylidene malononitrile yielded thiopyrane derivative11. The reaction pathway was assumed to followa preliminary formation of cabanion of the activemethylene compound 10 followed by a nucleophilicaddition at the ethylenic bond and cyclization via thenucleophilic addition of the mercapto group at thecyano group to give compound 11. Also, compound 9was allowed to react with acetylacetone and/or ethylacetoacetate in the presence of sulfur in the ethano-lic triethylamine solution to give the correspondingthienyl derivatives 12a,b, respectively. Furthermore,the reaction of compound 9 with carbon disulfideand 1,2-dibromoethane or 2 equivalents of methyl io-dide in a one-pot reaction using phase-transfer catal-ysis conditions [K2CO3/dioxan/TBAB] afforded com-pounds 13 and 14, respectively in good yields. Thestructure of products 9–14 was proved by elementalanalysis and spectral data (cf. Scheme 3, Table 1).

Compound 14 reacted with some bidentates,namely hydrazine hydrate, ethylene diamine,

Heteroatom Chemistry DOI 10.1002/hc

522 Moustafa and MohamedTA

BLE

1A

naly

tical

and

Spe

ctra

lDat

aof

the

New

Com

poun

ds

Mol

ecul

arM

P(◦

C)

Form

ula

Ana

lytic

alD

ata

Cal

cd/F

ound

Cry

stal

(Mol

ecul

arC

ompo

und

Sol

vent

Yie

ld(%

)w

eigh

t)C

HN

SIR

(cm

−1)

1H

NM

R,δ

(ppm

)

322

3E

than

ol81

C16

H15

N4O

PS

(342

.35)

56.1

355

.81

4.41

4.33

16.3

616

.17

9.36

9.21

3212

(NH

),12

46(C

O),

652

(PS

)11

.2(b

r,1H

,NH

),7.

95–7

.80

(dd,

2H,J

HH

=9

Hz,

orth

oto

P);

7.45

–7.4

0(m

,4H

,qui

noxa

line

prot

ons)

,6.9

(dd,

2H, J

HH

=9

Hz,

met

ato

P);

3.9

(s,3

H,O

CH

3),

2.2

(s,3

H,C

H3)

4a19

2E

than

ol63

C24

H24

N5O

PS

(461

.52)

62.4

562

.15

5.24

5.09

15.1

714

.95

6.94

6.83

3259

(NH

),12

39(C

–O),

650

(PS

)11

.9(b

r,1H

,NH

),7.

96–7

.85

(dd,

2H, J

HH

=9

Hz,

orth

oto

P);

7.40

–7.1

0(m

,9H

,qui

noxa

line

prot

ons

+P

h);6

.92

(dd,

2H,J

HH

=9

Hz,

met

ato

P);

5.1

(s,2

H,N

–CH

2–N

);4.

1(s

,2H

,CH

2);

3.9

(s,3

H,O

CH

3),

2.3

(s,3

H,C

H3)

4b18

4E

than

ol71

C23

H22

N5O

PS

(447

.49)

61.7

361

.48

4.95

4.81

15.6

515

.46

7.16

6.99

3259

(NH

),12

39(C

–O),

650

(PS

)11

.9(b

r,1H

,NH

),7.

92–7

.84

(dd,

2H, J

HH

=9.

2H

z,or

tho

toP

);7.

35–7

.05

(m,9

H,q

uino

xalin

epr

oton

s+

Ph)

;6.9

0(d

d,2H

,JH

H=

9.5

Hz,

met

ato

P);

5.1

(s,2

H,N

–CH

2–N

);3.

9(s

,3H

,O

CH

3),

2.3

(s,3

H,C

H3)

4c19

9–20

1D

ioxa

n69

C21

H24

N5O

2P

S(4

41.4

9)57

.13

56.8

25.

485.

2915

.86

15.6

57.

267.

0912

43(C

–O),

655

(PS

)7.

94–7

.80

(dd,

2H,J

HH

=9.

2H

z,or

tho

toP

);7.

4–7.

30(m

,4H

,qui

noxa

line

prot

ons)

,6.9

5(d

d,2H

, JH

H=

9.5

Hz,

met

ato

P);

5.1

(s,2

H,

N–C

H2–N

);3.

9(s

,3H

,OC

H3);

3.7–

3.4

(m,

4H,C

H2–O

CH

2);

2.9–

2.6

(m,4

H,

CH

2–N

–CH

2);

2.3

(s,3

H,C

H3)

4d18

3E

than

ol81

C21

H26

N5O

PS

(427

.50)

58.9

958

.69

6.13

5.96

16.3

816

.11

7.50

7.31

1239

(C–O

),64

4(P

S)

7.80

–7.7

0(d

d,2H

,JH

H=

9.2

Hz,

orth

oto

P);

7.60

–7.3

0(m

,4H

,qui

noxa

line

prot

ons)

,6.9

5(d

d,2H

,JH

H=

9.5

Hz,

met

ato

P);

5.1

(s,2

H,

N–C

H2–N

);3.

9(s

,3H

,OC

H3),

2.6

(q,4

H,

2NC

H2);

2.3

(s,3

H,C

H3);

1.1

(t,6

H,2

CH

3)

515

1E

than

ol66

C17

H17

N4O

2P

S(3

72.3

8)54

.82

54.4

94.

614.

4815

.04

14.8

18.

598.

3734

12(O

H),

1233

(C–O

),65

9(P

S)

8.9

(br,

1H,O

H);

7.82

–7.7

0(d

d,2H

, JH

H=

9H

z,or

tho

toP

);7.

60–7

.25

(m,4

H,q

uino

xalin

epr

oton

s),6

.95

(dd,

2H,J

HH

=9

Hz,

met

ato

P);

5.4

(s,2

H,C

H2);

3.9

(s,3

H,O

CH

3),

2.3

(s,

3H,C

H3)

617

3E

than

ol69

C17

H16

N4O

PS

Cl

(390

.82)

52.2

451

.89

4.12

4.01

14.3

314

.21

8.20

8.07

770

(C–C

l),64

9(P

S)

7.85

–7.7

0(d

d,2H

,JH

H=

9.2

Hz,

orth

oto

P);

7.55

–7.3

0(m

,4H

,qui

noxa

line

prot

ons)

,6.9

8(d

d,2H

,JH

H=

9.3

Hz,

met

ato

P);

6.2

(s,2

H,

CH

2);

3.9

(s,3

H,O

CH

3),

2.3

(s,3

H,C

H3)

7a14

3E

than

ol71

C20

H23

N4O

PS

2(4

30.5

3)55

.79

55.4

95.

385.

2213

.01

12.8

114

.89

14.7

712

33(C

–O),

692

(C–S

–C),

659

(PS

)7.

80–7

.65

(dd,

2H,J

HH

=9.

1H

z,or

tho

toP

);7.

40–7

.30

(m,4

H,q

uino

xalin

epr

oton

s),6

.97

(dd,

2H, J

HH

=9.

1H

z,m

eta

toP

);5.

2(s

,2H

,N

–CH

2–S

);3.

9(s

,3H

,OC

H3),

2.7

(t,2

H,

SC

H2);

1.7

(m,2

H,C

H2);

2.3

(s,3

H,C

H3);

1.1

(t,3

H,C

H3)


Synthesis and Reactions of [1,2,4,3]Triaza-phospholo[4,5-a]Quinoxaline Derivative 523TA

BLE

1C

ontin

ued

Mol

ecul

arM

P(◦

C)

Form

ula

Ana

lytic

alD

ata

Cal

cd/F

ound

Cry

stal

(Mol

ecul

arC

ompo

und

Sol

vent

Yie

ld(%

)w

eigh

t)C

HN

SIR

(cm

−1)

1H

NM

R,δ

(ppm

)

7b13

2E

than

ol80

C23

H27

N4O

PS

2(4

70.5

9)58

.69

58.4

15.

785.

5911

.90

11,7

113

.62

13.5

112

48(C

–O),

696

(C–S

–C),

659

(PS

)7.

80–7

.65

(dd,

2H, J

HH

=9

Hz,

orth

oto

P);

7.40

–7.3

0(m

,4H

,qui

noxa

line

prot

ons)

,6.9

5(d

d,2H

,JH

H=

9H

z,m

eta

toP

);5.

2(s

,2H

,N

–CH

2–S

);3.

9(s

,3H

,OC

H3),

3.3

(m,1

H,

SC

H);

2.3

(s,3

H,C

H3);

1.7–

1.2

(m,1

0H,

cycl

icC

H2)

7c17

3E

than

ol75

C23

H21

N4O

PS

2(4

64.5

4)59

.46

59.0

94.

554.

4012

.06

11.9

113

.80

13.5

912

36(C

–O),

696

(C–S

–C),

659

(PS

)7.

90–7

.78

(dd,

2H, J

HH

=9

Hz,

orth

oto

P);

7.65

–7.1

5(m

,9H

,qui

noxa

line

prot

ons

+P

h);

6.95

(dd,

2H,J

HH

=9

Hz,

met

ato

P);

5.7

(s,

2H,N

–CH

2–S

);3.

9(s

,3H

,OC

H3);

2.3

(s,3

H,

CH

3)

7d18

7E

than

ol59

C24

H20

N5O

PS

3(5

21.6

1)55

.25

54.8

63.

863.

7013

.48

13,2

918

.44

18.2

212

43(C

–O),

696

(C–S

–C),

662

(PS

)7.

92–7

.83

(dd,

2H, J

HH

=9.

2H

z,or

tho

toP

);7.

35–7

.05

(m,8

H,q

uino

xalin

e+

bezo

thia

zole

prot

ons)

;6.9

0(d

d,2H

,JH

H=

9H

z,m

eta

toP

);6.

1(s

,2H

,N–C

H2–S

);3.

9(s

,3H

,OC

H3);

2.3

(s,3

H,C

H3)

8a21

0C

hlor

o-fo

rm

86C

18H

17N

4O

2P

S(3

84.3

9)56

.24

55.8

64.

454.

2714

.57

14.2

98.

348.

2016

90(C

O),

1261

(C–O

),64

9(P

S)

7.85

–7.7

5(d

d,2H

,JH

H=

9.3

Hz,

orth

oto

P);

7.41

–7.3

4(m

,4H

,qui

noxa

line

prot

ons)

,6.9

5(d

d,2H

, JH

H=

9.5

Hz,

met

ato

P);

3.9

(s,3

H,

OC

H3),

2.4

(s,C

OC

H3);

2.3

(s,3

H,C

H3)

8b15

9E

than

ol86

C23

H19

N4O

2P

S(4

46.4

6)61

.87

61.5

64.

294.

1312

.55

12.4

07.

187.

0716

72(C

O),

1240

(C–O

),64

3(P

S)

7.90

–7.7

8(d

d,2H

, JH

H=

9H

z,or

tho

toP

);7.

65–7

.15

(m,9

H,q

uino

xalin

epr

oton

s+

Ph)

;6.

95(d

d,2H

,JH

H=

9H

z,m

eta

toP

);3.

9(s

,3H

,OC

H3),

2.3

(s,3

H,C

H3)

918

8E

than

ol78

C19

H16

N5O

2P

S(4

09.4

0)55

.73

55.3

63.

943.

7717

.10

16.9

17.

837.

6422

07(C

N),

1691

(CO

),12

49(C

–O),

644

(PS

)

7.85

–7.7

5(d

d,2H

, JH

H=

9.3

Hz,

orth

oto

P);

7.44

–7.3

4(m

,4H

,qui

noxa

line

prot

ons)

,6.9

0(d

d,2H

, JH

H=

9.5

Hz,

met

ato

P);

4.8

(s,2

H,

CH

2);

3.9

(s,3

H,O

CH

3);

2.3

(s,3

H,C

H3)

1020

3E

than

ol69

C19

H16

N5O

PS

2(4

25.4

6)53

.63

53.2

23.

793.

8716

.46

16.3

015

.07

14.8

322

11(C

N),

1233

(C–O

),11

90(C

S),

649

(PS

)

7.90

–7.7

8(d

d,2H

, JH

H=

9.3

Hz,

orth

oto

P);

7.45

–7.3

5(m

,4H

,qui

noxa

line

prot

ons)

,6.9

0(d

d,2H

, JH

H=

9.5

Hz,

met

ato

P);

4.2

(s,2

H,

CH

2);

3.9

(s,3

H,O

CH

3);

2.2

(s,3

H,C

H3)

1120

3E

than

ol72

C29

H22

N7O

PS

2(5

79.6

3)60

.08

59.7

23.

823.

6116

.91

16.6

711

.06

10.8

333

66,3

302

(NH

2),

2211

(2C

N),

664

(PS

)7.

90–7

.80

(dd,

2H, J

HH

=9

Hz,

orth

oto

P);

7.65

–7.2

5(m

,9H

,qui

noxa

line

prot

ons

+P

h);

6.90

(dd,

2H,J

HH

=9

Hz,

met

ato

P);

5(b

r,2H

,NH

2)

3.9

(s,3

H,O

CH

3);

3.5

(s,1

H,C

H);

2.3

(s,3

H,C

H3)

12a

249

DM

F81

C24

H22

N5O

3P

S2

(523

.56)

55.0

554

.68

4.23

4.08

13.3

713

.11

12.2

412

.05

3352

,328

6(N

H2),

1683

,165

9(2

CO

)66

1(P

S)

7.92

–7.7

8(d

d,2H

,JH

H=

9.1

Hz,

orth

oto

P);

7.45

–7.3

5(m

,4H

,qui

noxa

line

prot

ons)

,6.9

2(d

d,2H

,JH

H=

9.6

Hz,

met

ato

P);

5.4

(br,

2H,

NH

2)

3.9(

s,3H

,OC

H3);

2.5

(s,3

H,C

OC

H3);

2.2

(s,3

H,N

CC

H3);

2.0

(s,3

H,C

H3)


524 Moustafa and Mohamed

TAB

LE1

Con

tinue

d

Mol

ecul

arM

P(◦

C)

Form

ula

Ana

lytic

alD

ata

Cal

cd/F

ound

Cry

stal

(Mol

ecul

arC

ompo

und

Sol

vent

Yie

ld(%

)w

eigh

t)C

HN

SIR

(cm

−1)

1H

NM

R,δ

(ppm

)

12b

221

Eth

anol

59C

25H

24N

5O

4P

S2

(553

.59)

54.2

353

.92

4.37

4.19

12.6

512

.45

11.5

811

.37

3319

,329

9(N

H2),

1723

(CO

este

r),1

689

(CO

),66

1(P

S)

7.90

–7.8

0(d

d,2H

, JH

H=

9.1

Hz,

orth

oto

P);

7.44

–7.3

5(m

,4H

,qui

noxa

line

prot

ons)

,6.9

1(d

d,2H

,JH

H=

9.5

Hz,

met

ato

P);

5.4

(br,

2H,

–NH

2);

4.1

(q,2

H,C

H2);

3.9

(s,3

H,O

CH

3);

2.3

(s,3

HN

CC

H3);

2.0

(s,3

H,C

H3);

1.1

(t,

3H,C

H3)

1315

3E

than

ol85

C22

H18

N5O

2P

S3

(511

.57)

51.6

451

.35

3.54

3.33

13.6

913

.40

18.8

018

.61

2209

(CN

),16

65(C

O),

659

(PS

)7.

91–7

.80

(dd,

2H,J

HH

=9

Hz,

orth

oto

P);

7.42

–7.3

5(m

,4H

,qui

noxa

line

prot

ons)

,6.8

8(d

d,2H

, JH

H=

9.3

Hz,

met

ato

P);

3.3

(t,4

H,

J HH

=6.

1H

z,2S

CH

2);

3.9

(s,3

H,O

CH

3),

2.3

(s,3

H,C

H3)

1413

2E

than

ol79

C22

H20

N5O

2P

S3

(513

.59)

51.4

451

.08

3.92

3.77

13.6

313

.41

18.7

218

.55

2200

(CN

),16

61(C

O),

659

(PS

)7.

90–7

.77

(dd,

2H,J

HH

=9

Hz,

orth

oto

P);

7.48

–7.4

1(m

,4H

,qui

noxa

line

prot

ons)

,6.9

1(d

d,2H

, JH

H=

9.4

Hz,

met

ato

P);

3.9

(s,3

H,

OC

H3)

3.2

(s,6

H,2

SC

H3);

2.3

(s,3

H,C

H3)

1517

9E

than

ol74

C21

H20

N7O

2P

S2

(497

.53)

50.6

950

.31

4.05

3.90

19.7

019

.40

12.8

812

.67

3372

,332

1,32

46(N

H+

NH

2),

1661

(CO

);66

3(P

S)

12.0

(br,

1H,N

H);

7.90

–7.7

8(d

d,2H

, JH

H=

9.3

Hz,

orth

oto

P);

7.46

–7.3

8(m

,4H

,qui

noxa

line

prot

ons)

,6.8

8(d

d,2H

,JH

H=

9.2

Hz,

met

ato

P);

4.8

(br,

2H,N

H2);

3.9

(s,3

H,O

CH

3);

3.3

(s,3

H,S

CH

3);

2.3

(s,3

H,C

H3)

1616

6E

than

ol76

C22

H20

N7O

2P

S(4

77.4

8)55

.33

54.9

54.

224.

0920

.53

20.3

86.

716.

5132

11(N

H),

2203

(CN

),16

60(C

O),

651

(PS

)

12.0

(br,

1H,N

H);

11.2

(br,

1H,N

H);

7.90

–7.7

8(d

d,2H

, JH

H=

9.1

Hz,

orth

oto

P);

7.46

–7.3

6(m

,4H

,qui

noxa

line

prot

ons)

,6.9

0(d

d,2H

,J H

H=

9.5

Hz,

met

ato

P);

3.9

(s,3

H,O

CH

3);

3.2

(t,4

H, J

HH

=4.

6H

z,2C

H2);

2.3

(s,3

H,

CH

3)

17a

211

DM

F89

C26

H19

N6O

2P

S2

(542

.57)

57.5

557

.31

3.53

3.43

15.4

815

.39

11.8

111

.67

2209

(CN

),16

69(C

O),

653

(PS

)7.

92–7

.83

(dd,

2H, J

HH

=9

Hz,

orth

oto

P);

7.40

–7.0

5(m

,8H

,qu

inox

alin

e+

benz

o-th

iazo

lepr

oton

s);6

.90

(dd,

2H,J

HH

=9

Hz,

met

ato

P);

6.1

(s,1

H,

CH

);3.

9(s

,3H

,OC

H3);

2.3

(s,3

H,C

H3)

17b

221

DM

F78

C26

H19

N6O

3P

S(5

26.5

1)59

.30

58.9

13.

633.

4915

.96

15.7

96.

095.

9922

01(C

N),

1663

(CO

),66

0(P

S)

7.90

–7.8

3(d

d,2H

, JH

H=

Hz,

orth

oto

P);

7.38

–7.0

6(m

,8H

,qui

noxa

line

+be

nzox

azol

epr

oton

s);6

.88

(dd,

2H,J

HH

=9

Hz,

met

ato

P);

6.2

(s,1

H,C

H);

3.9

(s,3

H,O

CH

3);

2.3

(s,

3H,C

H3)

17c

194

Eth

anol

81C

26H

20N

7O

2P

S(5

25.5

2)59

.41

59.0

03.

833.

6818

.65

18.4

56.

105.

9832

69(N

H),

2201

(CN

),16

62(C

O),

650

(PS

)

11.1

(br,

1H,N

H);

7.92

–7.8

3(d

d,2H

, JH

H=

9.2

Hz,

orth

oto

P);

7.39

–7.0

4(m

,8H

,qu

inox

alin

e+

benz

imid

azol

epr

oton

s);6

.90

(dd,

2H,J

HH

=9

Hz,

met

ato

P);

6.1

(s,1

H,

CH

);3.

9(s

,3H

,OC

H3);

2.3

(s,3

H,C

H3)

aU

ncor

rect

ed.

bS

atis

fact

ory

mic

roan

alys

isob

tain

ed(C

:±0.

44,H

:±0.

19,N

:±0.

39,S

:±0.

35).

c Mea

sure

dby

Nic

olet

FT-

IR71

0sp

ectr

opho

tom

eter

.dM

easu

red

by1H

-NM

RLA

400

MH

z(J

eol)

atth

eA

ssiu

tUni

vers

ity.



SCHEME 2

o-aminothiophenol, o-aminophenol, and o-phenylenediamine in refluxing dimethyl-formamidefor about 38 h, to give compounds 15,16 and 17a–c,respectively. The reaction with hydrazine hydratewas assumed to proceed via a Michael addition ofone amino group at the ethylenic bond with the

elimination of methyl mercaptan followed by anucleophilic addition of the other amino group atthe cyano group to give compound 15, whereas thereaction with the other amino compounds proceedvia a nucleophilic attack of both the nucleophilicgroups at the ethylenic bond with elimination of



two molecules of methyl mercaptan to give com-pounds 16 and 17a–c, respectively (cf. Scheme 4and Table 1).

EXPERIMENTAL

Synthesis of Compound 3

Lawesson’s reagent (2.02 g, 0.005 mol) was addedto a solution of the hydrazone (0.01 mol) in 50 mLacetonitrile and refluxed until the evolution ofhydrogen sulfide was ceased (12 h). The reactionmixture was concentrated. After cooling, the formedprecipitate was filtered off and recrystallized fromthe appropriate solvent, yield 81% (cf. Table 1).

Synthesis of Compounds 4a–d: GeneralProcedure

Formaldehyde (1.5 mL, 40% solution) was addedto a solution of compound 3 (0.001 mol) in ab-solute ethanol (10 mL). The reaction mixture wasrefluxed for 1 h. After cooling to room temperature,the appropriate amine (0.001 mol) was added.The reaction mixture was refluxed for 4 h. Aftercooling, the formed precipitate was filtered andrecrystallized from the appropriate solvent to givethe corresponding Mannich bases 4a–d, yielding63%–81% (cf. Table 1).


Formaldehyde (1.5 mL, 40% solution) was added toa solution of compound 3 (0.001 mol) in absoluteethanol (10 mL). The reaction mixture was refluxedfor 1 h, the solvent was evaporated to dryness. Theformed solid was recrystallized from ethanol to givecompound 5, yield 66% (cf. Table 1).


Thionyl chloride (10 mL) was added dropwise tocompound 5 (0.005 mol), and the reaction mixturewas warmed on a water bath for 1 h. After cool-ing, the reaction mixture was poured on petroleumether (100 mL, 40/60◦C). The formed precipitate wasfiltered and recrystallized from ethanol to give com-pound 6, yield 69% (cf. Table 1).

Synthesis of Compounds 7a–d: GeneralProcedure

The appropriate thiol (0.01 mol) was added to analcoholic solution of sodium ethoxide (Na, 0.23 g,0.01 mol in 25 mL ethanol), then compound 6(0.01 mol) was added in small portions over 10 min.

The reaction mixture was refluxed for 4 h. Thesolvent was removed under reduced pressure. Theresidual solid was washed with cold water, filtered,and recrystallized from ethanol to give the corre-sponding sulfides 7a–d, yield 59%–80% (cf. Table 1).

Synthesis of Compounds 8a,b: GeneralProcedure

To a solution of compound 3 (0.005 mol) and triethy-lamine (0.005 mol) in dimethyl-formamide (30 mL),appropriate acid chloride was added in small por-tions over 5 min. The reaction mixture was refluxedfor 2 h. The solvent was removed under reduced pres-sure. The formed precipitate was filtered, washedwith cold water, and recrystallized from ethanol togive compounds 8a,b, yield 86% (cf. Table 1).


A mixture of compound 3 (0.01 mol), ethyl cyanoac-etate (0.01 mol), and sodium t-butoxide [Na (0.23 g,0.01 mol) in 40 mL t-butanol] was refluxed for 3h, evaporated in vacuo, and the separated solid wascollected by filtration, washed with water and recrys-tallized from ethanol, yield 78% (cf. Table 1).


A mixture of compound 9 (0.005 mol) and LR 1(0.005 mol) in dry toluene (50 mL) was refluxedfor 8 h. The reaction mixture was concentrated. Theformed precipitate was collected by filtration and re-crystallized from ethanol to give compound 10, yield69% (cf. Table 1).


Benzylidenemalononitrile (0.01 mol) was added to astirred mixture of compound 9 (0.1 mol) and a cat-alytic amount of piperidine in 50 mL of ethanol. Thereaction mixture was refluxed for 5 h, then concen-trated, and left to cool. The formed precipitate wasfiltered off and recrystallized from ethanol, yield 72%(cf. Table 1).

Synthesis of Compound 12a,b: GeneralProcedure

To a solution of compound 9 (0.005 mol) in ethanol(50 mL), 0.005 mol of acetylacetone and/or ethyl ace-toacetate and sulfur (0.005 mol) were added. The re-action mixture was treated with a catalytic amountof triethylamine (0.5 mL), refluxed for 5 h, evapo-rated in vacuo and the residual solid was collected



SCHEME 3

by filtration, washed with water and recrystallizedfrom the suitable solvent, yield 59.81% (cf. Table 1).

Synthesis of Compounds 13 and 14: GeneralProcedure

A mixture of compound 9 (0.01 mol), carbon disul-fide (0.012 mol), anhydrous potassium carbonate

(3 g), and a catalytic amount of tetrabutylammo-nium bromide (TBAB) in 50 mL of dry dioxanwas stirred for 15 min at 60◦C. To the formeddianionic ambident, 1,2-dibromoethane (0.01 mol)and/or methyl iodide (0.02 mol) was added. The re-action mixture was stirred for 3 h at 60◦C and then fil-tered, and the solvent was evaporated under reducedpressure. The residue was triturated with petroleum



SCHEME 4

ether (60–80◦C) and recrystallized from appropriatesolvent to give compounds 13 and14, yield 79% and85% respectively (cf. Table 1).

Synthesis of Compounds 15,16 and 17a–c:General Procedure

An equimolar mixture (0.005 mol) of compound15 and the proper amine in dimethylformamide(25 mL) was refluxed until the evolution of MeSHceased (∼38 h). The reaction mixture was con-centrated, and the precipitate solid was collectedby filtration, washed with pet. ether 40/60◦C, andrecrystallized from the suitable solvent to affordcompounds 15,16 and 17a–c, yield 74%–89%,respectively (cf. Table 1).

CONCLUSION

This article introduced a convenient and an effi-cient method for the synthesis of some new P-heterocycles. The pharmacological activity of the ob-tained compounds will be tested, expecting that itwill be biologically active.

REFERENCES

[1] Zhu, Z.; Saluja, S.; Drach, C. J.; Townsend, L. P. JChin Chem Soc 1988, 45(4), 465.

[2] El-Hawash, S. A.; Habib, N. S.; Fanaki, N. H. Phar-mazie 1999, 54, 808.

[3] Boido, A.; Vazzana, I.; Sparatore, F. Farmaco 1994,49, 97.

[4] He, L.-N.; Zhu, R.-X.; Chen, R.-Y.; Li, K.; Zham, Y.-J.Heteroatom Chem 1999, 10(2), 105.

[5] Chande, M. S.; Jagtap, R. S.; Sharma, R. N. Indian JChem B 1997, 36, 199.

[6] Reddy, C. D.; Berlin, K. D.; Reddy, R. S.; Raju, C. N.;Elmasri, M.; Subramanian, S. Phosphorus, SulfurSilicon 1993, 8, 61.

[7] Devendrahath Reddy, C.; Reddy, R. S.; Raju, N. In-dian J Chem B 1999, 39,735.

[8] Rao, L. N.; Reddy, V. K.; Reddy, C. D. HeteroatomChem 2000, 11(5), 323.

[9] Sankara Reddy, B.; Devendrahath Reddy, C. Indian JChem B 34, 1004.

[10] Zimmer, H.; Sill, A. Prog Drug Res 1964, 5, 150.[11] Moustafa, H. M. Phosphorus, Sulfur Silicon, 1999,

148, 131.[12] Moustafa, H. M. Phosphorus, Sulfur Silicon, 2000,

164,11.[13] Ghattas, A.-B. A. G.; Abd Allah, O. A.; Moustafa, H. M.

Phosphorus, Sulfur Silicon 2000, 157, 1.[14] Moustafa, H. M. Phosphorus, Sulfur Silicon 2003,

178, 1397.[15] Scheibye, S.; Pedersen, B. S.; Lawesson, S.-O. Bull

Soc Chim Belg 1978, 87, 299.[16] Ghattas, A.-B. A. G.; El-Khrisy, E.-E. A. M.; Lawesson,

S.-O. Sulfur Lett 1982, 69.



[17] Andersen, T. P.; Ghattas, A.-B. A. G;. Lawesson, S.-O.Tetrahedron 1983, 39, 3419.

[18] Pedersen, B. S.; Lawesson, S.-O. Tetrahedron 1979,35, 2433.

[19] El-Barbary, A. A.; Clausen, K.; Lawesson, S.- O. Tetra-hedron 1980, 36, 3309.

[20] El-Barbary, A. A.; Lawesson, S.- O. Tetrahedron 1981,37, 2647.

[21] Shabana, R.; Osman, F. H.; Atrees, S. S. Tetrahedron1994, 50, 6975.

[22] Shabana, R.; Atrees, S. S. Phosphorus, Sulfur Silicon1995, 105, 57.

[23] Asano, K.; Asai, S. Yakugaku Zasshi, 1958, 78,729.

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