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Studies on Ferrocene and its Derivatives, VI Cyclocondensation Reactions of Some Ferrocenyl Anils

Kh. M. Hassan Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt, A R E

Z. Naturforsch. 83b, 1508-1514 (1978); received May 31, 1978

Schiff Bases, Ferrocenyl Anils, Cyclocondensation Reactions

Ferrocenealdehyde have been condensed with some amines giving the corresponding Schiff bases. Cyclocondensation reaction of chloroacetylchloride (or thioglycolic acid) on ferrocenyl Schiff bases yielded ferrocenyl-/Mactams and ferrocenylthiazolidinones.

Despite the wide interest in ferrocene chemistry relatively few ferrocene derivatives have been tested for biological activities [1-5]. The aromatic charac-ter, stability, low toxicity [6] and ease of substitu-tion of ferrocene makes it ideal for use in drug design. Also, the sandwich structure of ferrocene renders it completely different from the conventional aromatic molecules usually attached to the ^-lactam and/or thiazolidinone nuclei.

A way from the forgoing properties of ferrocene derivatives, they are recommended as haematinies for the treatment of iron deficiency anaemia [7, 8].

Edwars et al. [9, 10] have been prepared a novel semi-synthetic derivatives of penicillin and cephalo-sporin in which the conventional phenyl or hetero-aromatic group has been replaced by a ferrocene moiety. The semi-synthetic antibiotic containing

ferrocene exhibit high antibiotic activity and some of them are potent ^-lactamase inhibitors. From this point of view, the work described in this investigation seems of interest to prepare some new ferrocenyl-/Mactams and/or ferrocenylthiazolidino-nes in which the ferrocenyl nucleus attached directly to the ^-lactam (or thiazolidione) ring which may be of medicinal interest.

Thus, ferrocenealdehyde have been condensed with some amines, namely, hydrazine, semicarb-azide, thiosemecarbazide; 2-aminopyridine and isatylidene-3-hydrazone in absolute alcohol giving symmetrical ferrocenylazometine (1); ferrocene-aldehyde semecarbazone (2) (or thiosemecarbazone) (3), ferrocenylidene-2-aminopyridine (4) and 3-(ferrocenaldazine)-2-oxendole (5) respectively, as follows:

Requests for reprints should be sent to Dr. Kh. M. Hassan, Chemistry Department Faculty of Science, Assiut University, Assiut, Egypt.

Kh. M. Hassan • Studies on Ferrocene and its Derivatives 1509

On the other hand, ferrocenealdehyde readily p-ferrocenylidenebenzenesulphonylpiperidine (or-condensed by fusion with salfanilylpiperidine [or- morpholine, -piperazine, -phenothiazine) and bis morpholine, piperazine, -phenothiazine and bis (p,p'-ferrocenylidenebenzenesulphonyl) piperazine. (salfanilyl) piperazine] yielded the corresponding The reaction is represented as follows:

FcCHO +

— H2N ^ g > S 0 2 - N ( 3

— H2N ^ S O 2 - N Q >

" h2N S q V SOo-N S

H2N - ( O Y S 0 2 - N \ H « 2 H 2 0

- H2N S O 2 - ( 3 - S O 2 ^ > N H 2

Fc-CH=N { 5 ) - 5 0 2 - l / y ; FcCH=N-(|£^S02 -N

FcCH= = N < 5 > S 0 2 - < ^H.2H20 5 FcCH = = N - ( 0 ) - S 0 2 - N

F c C H ^ S02- Q - S 0 2 ^ > N - C H - F C

10

The structure of compounds 1-5 and 6-10 is established from the combination of the micro-analytical data and the (IR) spectroscopy. The IR spectra of the compounds 1-5 showed a sharp absorption band at 1640-1620 cm - 1 for j>C=N group [11] and a band near 1100-1000 cm - 1 (unsubstituted cyclopentadienyl ring in ferrocene [12]). The com-pounds 6-10 showed beside the foregoing absorption bands, another band at about 1350-1340 cm - 1

vS02N group [11] and a broad absorption band at 3455 cm - 1 *>OH group (for 8), which was attributed to water of crystallization [13].

For several years, researches on ^-lactams stood as the only important contribution to this feild of heterocyclic chemistry. Thus, the tremendous im-petus have been given to the study of the reactivity of these compounds because of their relation to the structure of the naturally occurring penicillins. The cyclocondensation reaction of chloroacetyl chloride on ferrocenyl anils (1-5) and/or (6-10) have been carried out in dry dioxane in pressence of NEt3 as a catalyst afforded the ferrocenyl-/?-lactam deriva-tives (11-21). The reaction is represented as fol-lows:

1510 Kh. M. Hassan • Studies on Ferrocene and its Derivatives 1510

Cl-CH I

Fc-CH

C=0 0=C CH-Cl I I I N N CH-Fc

11

1 — 5 + CICH2 COCl | NEt3

Cl-CH -I

Fc-CH N

12

r 0 NH —<?—NH2

Cl-CH I

Fc-CH

C=0 I N —

13

NH NH.

Cl-CH I

Fc-CH

C=0

14

Fc-CH

Cl-CH C=0 0=C CH-Cl I I I

Fc -CH N N -

15 H

6 - 1 0 + ClCH2COCl

Cl-CH C = 0 I I Fc-CH N

NEt,

Cl-CH C = 0

S02-N

16

Cl-CH C = 0

N - ^ Q ^ - s o 2 V NH.2H20 ;

18

Cl-CH C = 0

Fc-CH N ~ ^ Q ) - S 0 2 - V 0

17

Cl-CH C = 0

Fc-CH N S O . - ^ ^S

19 O 0=C CH-Cl

Fc-CH N — ) . S 0 2 < 0 ) - N CH-Fc

20

Elemental analysis as well as spectroscopic at 1100-1000 cm - 1 for the unsubstituted cyclo-analysis of compounds 11-20 are in accordance with pentadiene ring in ferrocene [12]. the suggested structures. The IR spectra reveals an Several substituted thiazolidinones have been absorption band at about 1750-1743 cm - 1 for v C = 0 prepared and most of them are interested as local (monocyclic/S-lactam) [11], VSO2N at 1350 cm-1 and anesthetic agents [14]. The cyclocondensation

Kh. M. Hassan • Studies on Ferrocene and its Derivatives 1511

reaction of thioglycolic acid on ferrocenylazomethi- 20-30 h which give ferrocenylthiazolidinones (21-30) nes (1-10) was carried out in dry benzene for about as follows:

1 — 5 +SHCH2C00H

CH, CH-

C=0 0=C s c=o

Fc-CH N N CH-Fc ; Fc-CH

21 CHo

- N - N H - C - NH2

22

CH-SC=0

Fc-CH N NH C NH2

23

Fc-CH N

24

s c = o o=c

Fc-CH N N

25 ( T ^ N I

H

CH,

S I ° Fc-CH N — < ^ O y - S 0 2 N ^ y

26 CH2

S ^ C = 0

6 — 10 + SHCHjCOOH

CH,

S C=0

Fc-CH — N — S ° 2 ~

27 CH2

s N c « o

Fc-CH N — ( p y S °2 " ^ \lH-2H20 ; Fc-CH N

28 29

ö © SOr-N S

S C=0

CH2

o = c ^ N Fc-CH N — CH-Fc

30

Substituted thiazolidinones (21-30) have been definate absorption band at 1700-1690 cm - 1 which identified from the elemental and spectral (IR) data. attributed to vC = 0 group of 4-thiazolidinones The IR spectra of these compounds showed a well [15].

1512 Kh. M. Hassan • Studies on Ferrocene and its Derivatives 1512

Experimental The infrared absorption spectra were determined

with a Unicam SP 200 G spectrophotometer using KBr wafer technique. All melting points were un-corrected.

Preparation of ferrocenylazometines (1-10) a) Equimolar amounts of ferrocenealdehyde (in

case of 1 and 10 twice of aldehyde is used) and the corresponding amine was refluxed in dry alcohol in presence of piperidine for 10 h. The reaction mixture

Table I. Ferrocenylazomethines (1-10).

Compound No. Amine

m.p. [°C]

Yield [ % ]

Molecular formula

Analysis [ % ] Calcd (Found) C H N

1 Hydrazine 300 dec.

20 C2 2H2oN2Fe2 62.26 4.71 (62.01) (5.00)

6.60 (6.77)

2 Semecarbazide 141-142 76 C 1 2 Hi 3 N 3 OFe 53.13 4.79 (53.22) (5.02)

15.49 (15.50)

8 Thiosemecarbazide 157-158 70 Ci2Hi3N3SFe 50.17 4.52 (50.20) (4.70)

14.63 (14.80)

4 2 - Aminopyridine 119-120 38 Ci 6 Hi 4 N 2 Fe 66.20 4.82 (66.09) (5.10)

9.65 (10.02)

5 Isaty lidene -3 -hydrazone 102-103 60 Ci 9 Hi 5 N 3 OFe 63.86 4.20 (64.00) (4.30)

11.76 (12.03)

6 p - Sal fanilylpiperidine 270-271 45 C 2 2 H 2 4 N 2 0 2 SFe 60.55 5.50 (60.80) (5.60)

6.42 (6.60)

7 p-Salfanilylmorpholine 230-232 48 C 2 ]H 2 2 N 2 0 3 SFe 57.53 5.02 (57.60) (5.11)

6.39 (6.40)

8 p-Salfanilylpiperazine 310-311 52 C 2 i H 2 7 N 3 0 4 S F e 53.27 5.70 (53.33) (5.60)

8.87 ( 9.03)

9 p-Salfanilylphenothiazine 204-205 60 C 2 9 H 2 2 N 2 0 2 S 2 Fe 63.27 4.00 (63.31) (4.13)

5.09 (5.11)

10 Bis(p, p'-salfanilyl)piperazine 370-372 41 C 3 8 H 3 6 N 4 0 4 S 2 Fe 2 62.98 4.97 (63.05) (5.02)

7.73 (8.01)

Table II . Ferrocenyl-^-lactams (11-20).

Compound No.

m.p . [°C]

Yield [ % ]

Molecular formula

Analysis [ % ] Calcd (Found) C H N

11 180-182 10 C26H22N202Cl2Fe2 54.07 (54.10)

3.81 (4.01)

4.85 (5.00)

12 170-172 22 Ci4H1 4N302ClFe 48.41 (48.39)

4.03 (4.00)

12.10 (12.22)

13 102-103 18 Ci4Hi4N302SClFe 44.32 (44.40)

3.69 (4.00)

11.08 (11.11)

14 210-212 12 Ci8Hi5N2OClFe 59.01 (59.10)

4.09 (4.19)

7.65 (7.70)

15 217-218 14 C 2 3H 1 7N 30 3Cl 2Fe 54.11 (54.12)

3.33 (3.40)

8.23 (8.30)

16 178-179 13 C 2 4H 2 5N 20 3SClFe 56.25 (56.30)

4.88 (5.01)

5.46 (5.50)

17 203-204 16 C 2 3H 2 3N 20 4SClFe 53.69 (53.70)

4.47 (4.43)

5.44 (5.50)

18 190-192 13 C 2 3H 2 8N 30 5SClFe 50.27 (50.30)

5.10 (5.20)

7.65 (7.70)

19 136-138 12 C3iH2 3N203S2ClFe 59.42 (59.52)

3.67 (4.01)

4.47 (4.66)

20 230-232 15 C4OH3 9N406S2Cl2Fe2 : 52.28 (52.30)

4.24 (4.40)

6.10 (6.12)

Kh. M. Hassan • Studies on Ferrocene and its Derivatives 1513

was concentrated and cooled. The precipitate products was filtered off washed and crystallized from alcohol.

b) Equimolar amounts of ferrocenealdehyde (in case of 1 and 10 twice of aldehyde was used) and amine was fused at 180 °C for about 10 min. The solid mass was treteurated with ether then crystal-lized with alcohol.

The products from the method a) and b) have the same m.p. and no deprissation in mixed m.ps. and have the same I R spectra. The results are listed in Table I.

Synthesis of ferrocenyl-B-lactams (11-20) To a well stirred solution (0.01 mole) of the ferro-

cenylazomethines (1-10) and (0.02 mole) of NEt3 in dry dioxane added (0.02 mole) of monochloroacetyl chloride (in case of 1 and 10 twice quantity was used) dropwise at room temperature. After all the

Table III . Ferrocenylthiazolidin-4-ones (21-30).

Compound m.p. Yield No. [°C] [ % ]

21 140-142 8

22 118-120 11

23 98-100 13

24 186-188 14

25 145-146 16

26 201-202 18

27 180-182 20

28 210-211 17

29 172-174 18

30 230-231 12

[1] F. D. Popp and E. B. Moynahan, J. Heterocycl. Chem. 7, 351 (1970).

[2] J. L. Madinaveitia, Br. J. Pharmacol. 24, 352 (1965).

[3] B. Loev and M. Flores, J. Org. Chem. 26, 3595 (1961).

[4] F. D. Popp, S. Roth, and J. Kirby, J. Med. Chem. 6, 83 (1963).

[5] D. M. Wiles and T. Suprunchuk, Can. J. Chem. 46, 1865 (1968).

quantity of the chloroacetyl chloride was added, the mixture stirred for 10 h and left at room tem-perature for 6 days. The formed precipitate (NEt3 • HCl) was filtered off, washed thoroughly with dioxane. The filtrate was evaporated under reduced pressure. The residue was poured into ice cold acedified water. The precipitate formed was filtered off and crystallized from alcohol-benzene. The results are presented in Table II.

Preparation of ferrocenylthiazolidin-4-ones (21-30) A mixture of (0.02 mole) of the ferrocenylazo-

methines (1-10) and (0.02 mole of thioglycolic acid (in case of 1 and 10 twice volume was used) in 100 c. c. dry benzene was refluxed for 20 h. The solvent was distilled under reduced pressure till dryness. The residue was dissolved in ether and seeded. In some cases the thiazolidones separated directly from the benzene solution. The results are listed in Table III.

Analysis [ % ] Calcd (Found) C H N

60.46 4.65 5.42 (60.66) (4.72) (5.51) 48.69 4.34 12.17

(48.77) (4.44) (12.01) 46.53 4.15 11.63

(46.83) (4.50) (11.82) 59.34 4.39 7.69

(59.07) (4.42) (7.70) 54.65 3.76 8.31

(54.70) (4.00) (8.52) 56.47 5.09 5.49

(56.52) (5.11) (5.40) 53.90 4.68 5.47

(54.01) (4.77) (5.51) 50.45 5.30 7.67

(50.55) (5.40) (7.79) 59.61 3.84 4.48

(59.82) (4.21) (4.55) 54.42 4.31 6.04

(54.50) (4.60) (6.13)

[6] B. B. Shugaev and A. V. Bitkina, Toksikol. Gig. Prod. Neftekhim. Neftekhim Proizvod 1972, 224.

[7] British Patent. 819, 108, 26. 8. 59. Imperial Chemical Industries, Ltd.

[8] British Patent. 869, 504, 31 .5 . 61; 870, 949, 21. 6. 61. Imperial Chemical Industries, Ltd.

[9] E. I . Edwards, R. Epton, and G. Marr, J. Organomet. Chem. 85, C 23 (1975).

[10] E. I. Edwards, R. Epton, and G. Marr, J. Organomet. Chem. 107, 351 (1976).

Molecular formula

C26H24N202S2Fe

C 1 4Hi 5N 30 2SFe

Ci4Hi5N3OS2Fe

Ci8Hi6N2OSFe

C 2 3H 1 9N 30 3S 2Fe

C 2 4H 2 6N 20 3S 2Fe

C2 3H2 4N204S2Fe

C 2 3H 2 9N 30 5S 2Fe

C3iH2 4N203S3Fe

C42H4nN406S4Fe2

1514 Kh. M. Hassan • Studies on Ferrocene and its Derivatives 1514

[11] L. J. Bellamy, The Infrared Spectra of Complex Molecules, 2nd ed., Methuen and Co., Ltd., London 1958.

[12] A . Perjessy and S. Torna, Chem. Zvesti. 23, 533 (1969).

[13] A. A. W . Long and J. H . C. Nayler, J. Chem. Soc. C. 1971, 1920.

[14] H . D. Troutman and L. M. Long, J. Am. Chem. Soc. 70, 3436 (1948).

[15] A. R. Surrey, J. Am. Chem. Soc. 71, 3354 (1949).