A facile one-pot synthesis of some new spiro-thiazolidin-4-ones and benzimidazoles of biological interest

Article abstract of DOI:10.1080/10426500701555702

In a one-pot procedure, aromatic amines 1a-c, 9-fluorenone (2) and 2-mercaptoacetic acid (3) were converted into fluorenespiro-thiazolidinone derivatives 4a-c, which undergo condensation, oxidation and thiation to afford 6a-i, 7a-c, and 4-thioxo 8a-c, respectively. A new fluorenespiro-thiazolo- benzimidazole 10 was also obtained in one step via cyclocondensation of 1,2-phenylenediamine, 9-fluorenone and 2-mercaptoacetic acid. The obtained products seem to be interesting from the biological point of view.

Full text of DOI:10.1080/10426500701555702

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A Facile One-Pot Synthesis of
Some New Spiro-thiazolidin-4-
ones and Benzimidazoles of
Biological Interest
Nadia Hanafy Metwally a
a Department of Chemistry, Faculty of Science ,
University of Cairo , Giza, Egypt
Published online: 20 Feb 2008.
To cite this article: Nadia Hanafy Metwally (2007) A Facile One-Pot Synthesis
of Some New Spiro-thiazolidin-4-ones and Benzimidazoles of Biological Interest,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:1, 34-43, DOI:
10.1080/10426500701555702
To link to this article: http://dx.doi.org/10.1080/10426500701555702
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Phosphorus, Sulfur, and Silicon, 183:34–43, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701555702
A Facile One-Pot Synthesis of Some New
Spiro-thiazolidin-4-ones and Benzimidazoles
of Biological Interest
Nadia Hanafy Metwally
Department of Chemistry, Faculty of Science, University of Cairo,
Giza, Egypt
In
a one-pot procedure, aromatic amines 1a–c, 9-fluorenone (2) and 2-
mercaptoacetic acid (3) were converted into fluorenespiro-thiazolidinone derivatives
4a–c, which undergo condensation, oxidation and thiation to afford 6a–i, 7a–c, and
4-thioxo 8a–c, respectively. A new fluorenespiro-thiazolo-benzimidazole 10 was also
obtained in one step via cyclocondensation of 1,2-phenylenediamine, 9-fluorenone
and 2-mercaptoacetic acid. The obtained products seem to be interesting from the
biological point of view.
Keywords 2-Mercaptoacetic acid; 9-fluorenone; fluorenespiro[9.2ꢀ]-thiazolo[3ꢀ,4ꢀ-
a]benzimidazole; fluorenespiro[9.2ꢀ]-3ꢀ-aryl-thiazolidin-4-one derivatives
INTRODUCTION
2-Substituted-thiazolidin-4-one derivatives exhibit unusual high activ-
ity in vitro against Mycobacterium Tuberculosis (TB), as drugs for anti-
HIV and anticancer activity.1−4 Recently, a number of 4-thiazolidinones
having an 2-aryl substituted have been synthesized and found to ex-
hibit potent selective anti-plateret activating factor both in vitro and
in vivo.5 Thiazolo[3,4-a]benzimidazoles and their analogues were re-
ported to be potent anti-HIV agents.6,7 Spiroheterocyclic compounds
including thiazolidine moiety have also been shown to exhibit a vari-
ety of interesting biological activities.8–11 In continuation to our search
of new compounds with anticipated biological activity from accessible
starting materials,12–17 we report here a simple one-pot synthesis of
some new fluorenespiro-thiazolidin-4-one and fluorenespiro-thiazolo-
benzimidazole derivatives.
Received 5 May 2007; accepted 5 June 2007.
Address correspondence to Nadia Hanafy Metwally, Department of Chemistry, Faculty
of Science, University of Cairo, Giza, Egypt. E-mail: nhmmohamed@yahoo.com
34

Spiro-thiazolidin-4-ones and Benzimidazole
35
RESULTS AND DISCUSSION
Aromatic amines 1a–c, 9-fluorenone (2) and 2-mercaptocetic acid (3) re-
act as a one pot reaction to afford white solids. The structures assigned
for these solid compounds were proved based on elemental and spectral
analysis and structures 4a–c were assigned for them. For example, the
IR spectrum of the isolated product 4a showed absorption band near
1684 cm−1 corresponding to (CO) group. The 1H NMR spectrum of 4a re-
vealed a singlet signal at δ = 4.36 ppm attributed to methylene protons
and a multiplet at δ = 6.60–7.93 ppm corresponding to aromatic pro-
tons. Furthermore, the 13C NMR spectrum of 4a revealed signals at δ =
32.45, 75.13, and 171.39 ppm attributable to the methylene carbon, C-
2‘ and thiazolidine carbonyl carbon, besides the signals corresponding
to aromatic carbons (cf. Experimental Section and Scheme 1). Elemen-
tal analysis and mass spectral data agree with the proposed structures
4a–c.
SCHEME 1

36
N. H. Metwally
The methylene group in position-5 of thiazolidin-4ones was reported
to be active.18,19 Thus, compounds 4a–c undergo condensation with the
aldehydes 5a–c in refluxing ethanol under basic catalysis to yield the
5-arylidene derivatives 6a–i. The IR spectra of the isolated products
1
showed absorption bands near 1684 cm−1 due to CO group. The H
NMR spectra of these products revealed the disappearance of methy-
lene signals at δ = 4.36 ppm, and showed a multiplet at δ =∼ 6.65 ppm
attributable to olefinic and aromatic protons (cf. Experimental Section
and Scheme 2).
SCHEME 2
Oxidation of compounds 4a–c with a solution of KMnO4 under acidic
conditions at room temperature furnished the products 7a–c. The IR of
these products showed absorption bands near 1695 cm−1 corresponding
to CO group; 1341 and 1070 cm−1 corresponding to SO2 (asymmetrical
and symmetrical str.) group. The 1H NMR spectra of these isolated
products revealed a singlet at ∼δ = 5.0 ppm attributed to the active
methylene protons. Elemental analysis and mass spectra are in agree-
ment with the sulfone structures 7a–c (cf. Experimental Section and
Scheme 2).

Spiro-thiazolidin-4-ones and Benzimidazole
37
It has been reported that the biological activity thiazolidinone
derivatives was much improved upon transformed to the thioxo-
analogues.10,20 Therefore, we have converted compounds 4a–c into the
corresponding thioxo-derivatives 8a–c upon reaction with Lawesson’s
reagent under reflux in dry toluene for two hours (cf. Experimental
Section and Scheme 2).
It is also interesting to extend our work to synthesize a novel
spiro-thiazolo-benzimidazole via one-pot reaction of a mixture of 1,2-
phenylenediamine, 9-fluorenone and 2-mercaptoacetic acid in reflux-
ing toluene. From this reaction we could obtain a product of m.p.
168oC. Mass spectrum of this product showed m/e 326. The IR spec-
trum showed the disappearance of band at ∼1684 cm−1 correspond-
1
ing to the carbonyl group. The H NMR spectrum revealed a singlet
(2H) at δ = 4.99 ppm attributed to methylene protons, beside the ex-
pected signals of aromatic protons. Furthermore, the 13C NMR showed
a signal at δ = 45.28 ppm corresponding to methylene carbon and no
signal that can be attributed to a carbonyl carbon was shown at ∼δ =
170 ppm and appearance of signal at δ = 143.90 ppm corresponding
to imine carbon (C N), besides the signals corresponding to aromatic
carbons (cf. Experimental Section and Scheme 3). Elemental analysis
SCHEME 3

38
N. H. Metwally
1
and mass spectra agree with the IR, H NMR and 13C NMR spectra
data. Based on these collective data the fluorenespiro[9.2ꢀ]thiazolo[3ꢀ,4ꢀ-
a]benzimidazole structure 10 was assigned to this product. It is as-
sumed that the reaction proceeds through the formation of non-isolable
Schiff’s base, followed by addition of the thiol to the C N bond to af-
ford the non-isolable 9, which in role, undergoes ring closure in situ
with the elimination of water to afford 10 (cf. Experimental Section and
Scheme 3).
EXPERIMENTAL
Melting points were determined on an electrothermal (9100) apparatus
and are uncorrected. The IR spectra were recorded as KBr pellets on a
Perkin Elmer 1430 spectrophotometer. 1H NMR and 13C NMR spectra
were recorded in deuterated dimethylsulfoxide at 300 MHz on a Varian
Gemini NMR spectrometer using tetramethylsilane as internal refer-
ence, and results are expressed as δ values. Mass spectra were taken
on a Shimadzu GCMS-QP 1000 Ex mass spectrometer at 70 eV. Ele-
mental analyses were carried out at the Microanalysis Center of Cairo
University, Giza, Egypt.
Fluorenespiro[9.2ꢀ]-3ꢀ-aryl-thiazolidin-4-ones 3a–c—General
Procedure
A mixture of the appropriate amines 1a–c (20 mmol), 9-fluorenone
(1.80 g, 10 mmol) and 2-mercaptoacetic acid (2.76 g, 30 mmol) in
25 ml dry toluene was refluxed for 8 h, and the solvent was evapo-
rated till dryness under reduced pressure and the residue was trit-
urated with ether. The ether layer was washed with sodium bicar-
bonate solution (1–2%) and finally with H2O. The organic layer was
dried over sodium sulfate and evaporated to dryness at reduced pres-
sure. The solid so formed was collected by filtration and recrystallized
from ethanol to give the title compounds, respectively (cf. Tables I and
II).
5ꢀ-Arylidene-fluorenespiro[9.2ꢀ]-3ꢀ-aryl-thiazolidin-4-ones
6a–i—General Procedure
A mixture of compounds 4a–c (10 mmol) and aldehydes 5a–c (10 mmol)
in 25 ml sodium ethoxide solution was refluxed for 1 h, left at room
temperature, and the solid so formed was filtered off and recrystallized
from ethyl alcohol/dioxin (cf. Tables I and II).

39

40

Spiro-thiazolidin-4-ones and Benzimidazole
41
TABLE II Spectral Data of the Newly Synthesized Compound
Compound No. Spectral data, IR (cm−1), 1H NMR, and 13C NMR
4a
IR: 1684 (C O);1H NMR: (DMSO-d6)δ 4.36 (s, 2H, CH2) and
6.60–9.93 (m, 13H, Ar-H);13C NMR: (DMSO-d6)δ 32.45, 75.13,
122.44, 125.33, 127.69, 128.32, 128.47, 129.87, 136.28, 138.31,
145.62, and 171.39
4b
4c
6a
6b
6c
6d
6e
6f
IR: 1682 (C O); 1H NMR: (DMSO-d6)δ 3.57 (s, 3H, OCH3), 4.38 (s,
2H, CH2), and 6.61–7.77 (m, 12H, Ar H)
IR: 1683 (C O); 1H NMR: (DMSO-d6): δ 4.38 (s, 2H, CH2) and
6.99–7.88 (m, 12H, Ar H)
IR: 1683 (CO); 1H NMR: (DMSO-d6)δ 7.03–7.81 (m, 19H, CH and
Ar H)
IR: 1684 (C O); 1H NMR: (DMSO-d6)δ 3.57 (s, 3H, OCH3) and
6.61–7.77 (m, 18H, CH and Ar H)
IR: 1684 (C O); 1H NMR: (DMSO-d6)δ 6.70–7.80 (m, 18H, CH, and
Ar H)
IR: 1684 (C O); 1H NMR: (DMSO-d6)δ 3.57 (s, 3H, OCH3) and
6.75–7.86 (m, 18H, CH, and Ar H)
IR: 1685 (C O); 1H NMR: (DMSO-d6)δ 3.56, 3.57 (s, 6H, OCH3) and
6.71–7.90 (m, 17H, CH and Ar H)
IR: 1685 (C O); 1H NMR (DMSO-d6)δ 3.57 (s, 3H, OCH3) and
6.74–7.93 (m, 17H, Ar H)
6g
6h
IR: 1684 (C O);1H NMR: (DMSO-d6)δ 7.11–7.86 (m, 18H, CH, and
Ar H)
IR: 1685 (C O); 1H NMR: (DMSO-d6)δ 3.57 (s, 3H, OCH3) and
6.71–7.88 (m, 17H, CH, and Ar H)
6i
7a
IR: 1684 (C O);1H NMR: (DMSO-d6): δ 6.71–7.91 (m, 17H, Ar H)
IR: 1695 (C O), 1340, 1070 (SO2); 1H NMR: (DMSO-d6): δ 5.07 (s,
2H, CH2)and 7.06–7.86 (m, 13H, Ar H)
7b
7c
8a
8b
8c
10
IR: 1696 (C O), 1341, 1072 (SO2); 1H NMR: (DMSO-d6)δ 3.56 (s,
3H, OCH3), 5.10 (s, 2H, CH2), and 6.80–7.88 (m, 12H, Ar H)
IR: 1696 (C O), 1341, 1072 (SO2); 1H NMR: (DMSO-d6)δ 5.12 (s,
2H, CH2) and 6.95–7.90 (m, 12H, Ar H)
1H NMR: (DMSO-d6)δ 4.95 (s, 2H, CH2) and 7.02–7.91 (m, 13H,
Ar H)
1H NMR: (DMSO-d6)δ 3.56 (s, 3H, OCH3), 4.96 (s, 2H, CH2), and
7.10–7.85 (m, 12H, Ar H)
1H NMR: (DMSO-d6)δ 5.0 (s, 2H, CH2) and 7.12–7.90 (m, 12H,
Ar H)
1H NMR: (DMSO-d6)δ 4.99 (s, 2H, CH2) and 7.33–7.94 (m, 12H,
Ar H); 13C NMR: (DMSO-d6) 45.28, 48.40, 118.30, 124.49,
127.75, 128.50, 128.70, 130.20, 133.93, 137.18, 138.30, 143.90,
and 145.70

42
N. H. Metwally
Fluorenespiro[9.2ꢀ]-3ꢀ-aryl-thiazolidin-4-one-1ꢀ,1ꢀ-dioxides
7a–c—General Procedure
To a solution of 4a–c (10 mmol) in 10 ml of glacial acetic acid was added
a saturated solution of potassium permanganate (5 ml) in ice bath for
10 min; and, a saturated solution of sodium hydrogen sulfite was added
till the solution was faded. The precipitate so formed was filtered off,
washed well with water, and crystallized from the appropriate solvent
(cf. Tables I and II).
Fluorenespiro[9.2ꢀ]-3ꢀ-aryl-thiazolidin-4-thiones
8a–c—General Procedure
A mixture of 4a–c (10 mmol) and Lawesson’s reagent (0.44 g, 10 mmol)
in dry toluene (15 mL) was heated at reflux for 2 h. The reaction mixture
was filtered off, and the solid so formed was filtered off and recrystal-
lized from methanol (cf. Tables I and II).
Fluorenespiro[9.2‘]thiazolo[3ꢀ,4ꢀ-a]benzimidazole
(10)—General Procedure
A mixture of 1,2-phenylenediamine (2.16 g, 20 mmol), 9-fluorenone
(1.80 g, 10 mmol) (2), and 2-mercaptoacetic acid (3) (2.76 g, 30 mmol)
in 25 ml dry toluene was refluxed for 48 h, and then concentrated till
dryness under reduced pressure and the residue was taken-up in ether.
The ether layer was washed with sodium bicarbonate solution (1–2%)
and finally with H2O. The organic layer was dried over sodium sulfate
and evaporated to dryness at reduced pressure to afford 10 (cf. Tables
I and II).
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