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Synthesis of Some New Spiro Heterocyclic Nitrogen Compounds, II

Kh. M. Hassan, A. K. El-Shafei*, and H. S. El-Kashef Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt

* Chemistry Department, Faculty of Science, Sohag, Egypt

Z. Naturforsch. 38b, 1 5 I 5 - I 5 I 9 (1978); received July 4, 1978

Spiro Heterocyclic Nitrogen Compounds, Synthesis

The synthesis of spiro-y-amino(or y-chloro)-/Mactams and spiro-4-thiazolidones by the cycloaddition reaction of 3-isatylidene anil derivatives, phthalylglycyl chloride (or chloro-acetyl chloride) and/or mercaptoacetic acid has been investigated. 3-Isatylidene anils were prepared by the reaction of isatine with substituted aniline, a-naphthylamine, 2-aminothiazoles, 2-aminothiadiazoles and 2-aminopyridine, respectively.

Owing to the potential medicinal importance of azetidin-2-ones that have the lactam nitrogen atom at a ring junction [1], the interest of various groups has been directed in our laboratory towards synthe-sizing the so-called functionally substituted spiro /^-lactams. The observations on chemotherapeutic efficiency of 4-thiazolidones as local anethetic and anticonvulsant agents [2, 3], are of interest and justify a detailed study of the toxicological prop-erties of the most active compounds.

In this communication, the basic synthetic approach to the hitherto unreported spiro hetero-cycle was established by the following routes (i) preparation of the key intermediates, 3-isatylidene anils (1-4); (ii) cycloaddition of the key inter-mediates on phthalyglycyl chlorides (or chloroacetyl chloride) and (iii) cyclocondensation of the key intermediates on mercaptoacetic acid.

The reaction of isatine with substituted aniline, a-naphthylamine, 2-aminothiazoles, 2-aminothia-diazoles and 2-aminopyridine was carried out giving rise to the 3-isatylidene anils (1-4) in a quantitative yields.

N « - 0 - « ,

a Ar = C6H5

b Ar = O -CH3 -C6H;

C Ar = p-CH3-C6H4

d Ar = C1 0H7

H 2

Ri a C6H5

b C 6H 5

c p-CH3- C6H4

R 2

H CH3

H

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

k - C T

H 3

r3

a CH3

b C 2 H 3 c C 3 H 7

d C 6H 5

e CH 2 -C 6H 5

in m

cx? JO

The structure of the compounds 1 -4 was estab-lished from their microanalytical data as well as the IR spectrum which showed a well defined band in the region 1640-1580 cm"1 due to vC=N. The cyclic imide group shows its absorption as two bands at 1800-1790 cm-1 region and between 1715-1705 cm-1.

The cycloaddition reaction of phthalylglycyl chloride on 3-isatylidene anils (1-4) was carried out in dry benzene using triethylamine as an acid binding agent, giving the corresponding spiro-[indolino-3,4-azetidine]-3'-N-phthalyl-2,2'-dione de-rivatives (5-8), respectively, in good yields. The reaction can be illustrated as follows:

1a,b,c,d

2a 3a 4

II %

C \ N-CHoCOCl

/

TEA

c-̂ 0

Oc -c=o

-N-Ar

t o

_c=o

£3 o H

Sa,b,c,d

=0

1516 Kh. M. Hassan et al. • Synthesis of Some New Spiro Heterocyclic Nitrogen Compounds

H

-c^o

CG c=o

N N H - U - CH,

^0

7 a

Cc -c=o

>=0

Hydrazinolysis of compounds 5 -8 using hydrazine hydrate and HCl giving the corresponding spiro-[indolino-S^'-azetidinej-S'-amino^^'-dione hydro-chlorides (9-12).

5a,b,C|<l Sa 7a ft

NH2.NH2.2H20 HCl

HCI.NH2- c=o

N-Ar

HCL. NU,-

H 9 a,b,c,d

a C=o

N // W S'

H 10 a

HCL. NH2 ec c=o I N N Uj-

HCL.NH,

CH, / t O

H 11a

Oc I H

- 0 0

•O

The structure of the two series 5-8 and 9-12 was established from their analytical data and IR spectra. Compounds 5-8 show an absorption peak at 1820-1790 cm-i which is due to v C = 0 (phthalyl) and at 1730-1700 cm - 1 which can be assigned for v C = 0 (monocyclic ^-lactam). However, the IR spectra of compounds 9-12 is characterized by a broad band near 3300 cm - 1 of the vNH2 as well as a band at 1740-1710 cm-1 which attributed to j>C=0 (monocyclic ^-lactam).

Chloroacetyl chloride was reacted with compounds 2 -4 in dry dioxane in presence of TEA. The spiro-[indolino-3,4'-azetidine]-3'-chloro-2,2'-dione deriva-tives (13-15) were separated from the reaction mixture.

The structure of compounds 13-15 was confirmed by both the analytical data and IR spectra. The spectra of these compounds showed a characteristic absorption peaks at 1750-1730 cm - 1 and between

780-750 cm - 1 which may be attributed to *>C=0 (monocyclic /^-lactam) and vC-Cl, respectively. The cyclic imide group shows two absorption peaks at 1800-1790cm-1 region and between 1715-1705cm-1.

2 a, b, c TEA 3 a, c,d + ClCHaCOCl • 4

H Cl-oc n ci-

iCR to Oct

-c=o N N

n J >

H H 13a,b,c, 14a, c j ,

Cl-

Oc -c=o

•o 15

The action of mercaptoacetic acid on 3-isatylidene anils [4] (2-4) was studied. Thus, mercaptoacetic acid was cyclocondensed with 2-4 in dry benzene by stirring the reaction mixture over periods of time ranging from 6 to about 24 h whereas a desirable yields of spiro[indolino-3,2'-thiazolidone]-2,4'-dione derivatives (16-18) were obtained. The reaction can be formulated as follows:

2a,b ,c —HoO 3 a, c, d + HSCHaCOOH 4

5 ^ J ~ T R l

N I H 16a,b,c

t=0

C^C^N N

t=o

17a,c,d s - f V

|| I - N ' NT i

H 18

The structure of spiro-4-thiazolidones was confirmed by a combination of elemental and spectral analysis. The infrared spectra are characterized by a band in the region 1720-1695 cm - 1 which is due to the v C = 0 group.

The reactivity of the 3-isatylidene anils (1-4) towards cycloaddition reactions decreases on going

1517 Kh. M. Hassan et al. • Synthesis of Some New Spiro Heterocyclic Nitrogen Compounds

from anilino, pyridino, thiazolo to thiadiazolo, isatylidene anils. This observation was established from the reaction conditions especially with mercaptoacetic acid. The time of stirring ensuring the cycloaddition reaction increases from compounds having aromatic to those having heteroaromatic ring residue (anilino- to pyridino-). The introduction of further heteroaromatic ring atoms raises the time of stirring up to about 24 h. However, this behav-iour may be interpreted as being due to the increased electron accepting [5, 6] character in the order thiadiazolo > thiazolo > pyridino > anilino moeities. This, in turn, tends to decrease the residual negative charge on the N atom of the C = N linkage and consequently a lower reaction rate since these reactions are electrophilic in nature.

Experimental All melting points were uncorrected. The IR

spectra were recorded on a Pye Unicam SP 200 G spectrophotometer, using KBr discs.

2-Aminothiazoles [7] and 2-aminothiadiazoles [8] These compounds were prepared according to

procedures reported in the literature.

3-Isatylidene anil derivatives (1-4) A pure sample of amine (0.05 mole) together with

the isatin was fused on a small flame for about 3 -4 min and the molten mass was left to cool giving a solid mass. This was washed several times with petroleum ether and then crystallised from the proper solvent. The results are listed in Table I.

Spiro[indolino-3,4'-azetidineJ-3'-amino-2,2'-dione hydrochloride derivatives (9-12)

Phthalylglycyl chloride (0.01 mole) in dioxane (10 ml) and triethylamine (0.01 mole) were refluxed with 3-isatylidene anil derivatives (1-4), (0.01 mole) for 2 h. The precipitated triethylamine hydro-chloride was filtered, the filtrate evaporated in vacuo, and the residue was crystallized from the proper solvent to give the spiro[indolino-3,4'-azetidine]-3'-N-phthalyl-2,2'-dione derivatives (5-8).

0.5 g of 5-8 in 30 ml ethanol was refluxed with hydrazine hydrate (10 ml) for 1 h, the reaction mixture was evaporated, the dry residue warmed at 50 °C for 10 min with 25 ml" of 2 N HCl, and allowed to stand at room temperature for 30 min. The precipitated phthalichydrazide was filtered and the filterate evaporated in vacuo to complete dryness to give 9-12. The results are listed in Table II.

Tab. I . 3-Isatylidene anil derivatives (1-4).

Compound Ar RI R2 R3 m.p. Molecular Calcd (Found) Compound [°C] formula C [ % ] H [ % ] N [ % ]

la C6H5 228 CI4HION20 75.68 4.50 12.61 (75.42) (4.36) (12.41)

lb O-CH3-C6H4 196 C15H12N2O 76.27 5.08 11.86 (76.01) (5.15) (11.95)

lc P-CH3-C6H4 225 C15H12N2O 76.27 5.08 11.86 P-CH3-C6H4 (76.14) (5.00) (12.02)

ld CIOH7 252 C18H12N2O 79.41 4.41 10.29 (79.62) (4.20) (10.18)

2a C6H5 H 135 CI7HnN3SO 66.89 3.61 13.77 (66.75) (3.55) (13.59)

2b C6H5 CH3 208 CI8HI3N3SO 67.71 4.08 13.17 (67.59) (4.22) (13.05)

2c P-CH 3 -C 6 H 4 H 120 CI8HI3N3SO 67.71 4.08 13.17 P-CH 3 -C 6 H 4 (67.88) (4.18) (13.25)

Ba CH3 180 CHH8N4SO 45.10 3.29 22.95 (45.00) (3.17) (23.09)

3b C2H5 215 CI2HI0N4SO 55.81 3.88 21.71 (56.00) (3.78) (21.52)

3c C3H7 145 CI3HI2N4SO 57.35 4.41 28.59 (57.49) (4.35) (28.36)

3d CÖHÖ 165 C18H10N4SO 62.75 3.27 18.30 (62.59) (3.14) (18.45)

3e CH2 • CßH4 135 CI7HI2N4SO 63.75 3.75 17.50 (63.64) (3.66) (17.65)

4 185 C I 3 H 9 N 3 0 69.96 4.04 18.82 (70.07) (4.20) (18.96)

1518 Kh. M. Hassan et al. • Synthesis of Some New Spiro Heterocyclic Nitrogen Compounds

Table II . Spiro[indohno-3,4'-azetidine]-3'-amino-2,2'-dione hydrochloride derivatives (9-12).

Compound A t RI R2 R3 m.p. [°C]

Molecular formula

Calcd. (Found) C [ % ] H [ % ] N [ % ]

9a CÖHÖ > 3 0 0 Ci6HI4N302C1 60.86 4.44 13.31 (60.69) (4.39) (13.35)

9b o • CH 3 • C6H4 175 CI7HI6N302C1 61.91 4.86 12.75 (61.87) (4.72)(12.78)

9c v • CH 3 • CßHI 158 CI7H1 6N302C1 61.91 4.86 12.75 (61.78) (4.59) (12.66)

9d C10H7 142 C20H16N3O2CI 65.66 4.38 11.49 (65.54) (4.22) (11.54)

10 a C6H5 H 212 Cx8Hi5N4S02Cl 56.03 3.88 14.49 (56.18) (3.65) (14.60)

11a CH3 198 CI3H12N5S02C1 46.22 3.56 20.74 (46.35) (3.42) (20.65)

12 168 CI5HI3N402C1 56.87 4.11 17.69 (56.66) (4.30) (17.80)

Spiro[indolino-3,4'-azetidine]-3'-chloro-2,2'-dione derivative (13-15)

To a well stirred solution of (0.01 mole) of the 3-isatylidene anil derivatives (2-4) and (0.01 mole) of triethylamine in dry benzene added (0.01 mole) of chloroacetylchloride dropwise at room tem-perature. After all the quantity of chloroacetyl-chloride was added, the mixture was stirred for extra 5 h and left at room temperature for three days. The precipitated triethylamine hydrochloride was filtered off and washed thoroughly with dry benzene. The combined solvent and filterate was washed with dilute HCl then with water for several times, then dried over anhydrous magnesium sul-

phate. After Alteration, the solvent was evaporated in vacuo. The residue was precipitated by ether then crystallized from the proper solvent. The results are listed in Table III.

Spiro[ indolino - 3,2'-thiazoli done J-2,4'-dione derivatives (16-18)

0.015 mole of mercaptoacetic acid was added to a well stirred solution of 0.01 mole of 3-isatylidene anil derivatives (2-4) in 50 ml of dry benzene. The mixture was stirred over periods of time varying from 6 h to about 24 h. The product which precipi-tated was filtered off and crystallised from the proper solvent. The results are listed in Table IV.

Table III . Spiro[indolino-3,4'-azetidine]-3'-chloro-2,2'-dione derivatives (13-15).

Compound RI R2 R3 m.p. t°C]

Molecular formula

Calcd (Found) C [ % ] H [ % ] N [ % ] C l [ % ]

13 a C6H5 H 220 CI9HI2N3S02C1 59.76 3.15 11.01 9.31 (59.56) (3.22) (11.12) (9.22)

13 b C6H5 CH3 202 C20H14N3SO2CI 60.68 3.54 10.62 8.98 (60.72) (3.60) (10.54) (8.90)

13 c CH3CEH4 H 170 C2OHI4N3S02C1 60.68 3.54 10.62 8.98 (60.52) (3.45) (10.70) (8.92)

14a CH3 138 CI3H9N4S02C1 48.67 2.81 17.47 11.08 (48.56) (2.76) (17.54) (11.15)

14c C3H7 162 CI5HI3N4S02C1 51.65 3.73 16.07 10.19 (51.72) (3.67) (16.18) (10.22)

14 d CÖHÖ 225 CI8HHN4S02C1 56.47 2.88 14.64 9.28 (56.52) (2.78) (14.80) (9.32)

15 112 CI5HI„N302C1 60.10 3.34 14.02 11.85 (60.28) (3.21) (14.19) (11.90)

1519 Kh. M. Hassan et al. • Synthesis of Some New Spiro Heterocyclic Nitrogen Compounds

Table IV. Spiro[indolino-3,2'-thiazolidone]-2,4'-dione derivatives (16-18).

Compound RI R 2 R 3 m.p. [°C]

Molecular formula

Calcd (Found) C [ % ] H [ % ] N [ % ]

16 a CEHS H 235 Ci9Hi 3N 3S 20 2 60.16 3.43 11.08 (59.98) (3.22) (11.21)

16b CEH5 CH3 312 C2 0H1 5N3S2O2 61.07 3.82 10.69 (61.12) (3.70) (10.72)

16c CH3 • CßHI H 105 C2 0HI5N3S2O2 61.07 3.82 10.69 (61.22) (3.95)(10.55)

17 a CH3 > 3 0 0 CI3HION4S202 49.06 3.14 17.61 (49.20) (3.23) (17.65)

17 b C3H7 145 CI5HI4N4S202 52.02 4.05 16.18 (52.17) (4.19) (16.29)

17c C6H5 122 C 1 8 HI 2 N 4 S 2 0 2 56.84 3.16 14.74 (56.92) (3.30) (14.80)

18 124 CI 5 H N N 3 S0 2 60.61 3.94 14.14 (60.50) (3.88) (14.21)

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