A convenient synthesis of ω-(2-aryl-4-oxothiazolidin-3-yl) alkylphosphonic acids via in situ-generated arylideneaminoalkylphosphonic acids

Article abstract of DOI:10.1080/10426500903567539

ω-(2-Aryl-4-oxothiazolidin-3-yl)alkylphosphonic acids are prepared in an easy workup procedure by the addition of methyl mercaptoacetate to in situ-generated arylideneaminoalkyl phosphonic acids. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500903567539

Phosphorus, Sulfur, and Silicon, 185:2233–2237, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903567539
A CONVENIENT SYNTHESIS OF
ω-(2-ARYL-4-OXOTHIAZOLIDIN-3-YL)ALKYLPHOSPHONIC
ACIDS VIA IN SITU–GENERATED
ARYLIDENEAMINOALKYLPHOSPHONIC ACIDS
Dariusz Cal
Department of Organic and Applied Chemistry, University of Ło´dz´, Ło´dz´, Poland
ω-(2-Aryl-4-oxothiazolidin-3-yl)alkylphosphonic acids are prepared in an easy workup pro-
cedure by the addition of methyl mercaptoacetate to in situ–generated arylideneaminoalkyl
phosphonic acids.
Keywords
Aminophosphonic acids; arylideneaminophosphonic acids; cyclizations;
4-thiazolidinones
INTRODUCTION
4-Thiazolidinones constitute a class of compounds that exhibit very useful proper-
ties and utilities. For instance, they have been demonstrated to possess a broad spectrum
of biological activities such as antitumor,1 antibacterial,2 antifungal,2 antitubercular,3 anti-
HIV-RT,4 antiinflammatory,5 and many others.6 It has been shown that the presence of a
phosphonyl group could influence the biological functions of heterocyclic systems.7 Some
synthetic approaches to 4-thiazolidinones bearing a dialkylphosphonic ester moiety have
already been reported. One of the methods requires the reaction of 5-arylidene-2-thioxo-
4-thiazolidinones with phosphonoacetates and leads to the fused-thiazole derivatives.8 An-
other method is based on the reaction of imidoyl phosphonates with mercaptoacetic acid
or its alkyl esters.9,10 The phosphonyl functionalized 4-thiazolidinones can also be pre-
pared by the reaction of phosphonylated Schiff bases generated from aromatic aldehydes,
aminophosphonic acid esters, and mercaptoacetic acid;11 however all these methods lead
to phosphonic esters.
In this article, we provide a new, one-pot approach to ω-(2-aryl-4-oxothiazolidin-3-
yl)alkylphosphonic acids.
Received 28 October 2009; accepted 17 December 2009.
This work is dedicated to my mentor, Prof. Romuald Bartnik, University of Ło´dz´, Ło´dz´, Poland, on the
occasion of his 70th birthday.
This research project was supported by the Faculty of Chemistry, University of Ło´dz´.
Address correspondence to Dariusz Cal, Department of Organic and Applied Chemistry, University of Ło´dz´,
Tamka 12, PL 91-403, Ło´dz´, Poland. E-mail: darekcal@uni.lodz.pl
2233

2234
D. CAL
RESULTS AND DISCUSSION
Previously we have established an efficient route to N-benzyl functionalized
aminoalkylphosphonic acids and ω-[(arylphosphonomethyl)amino]alkylphosphonic acids
via in situ–generated arylideneaminoalkylphosphonic acids.12,13 Now we have used these
reactive arylideneaminoalkylphosphonic acids in the synthesis of 4-thiazolidinones bearing
a phosphonic acid function. As shown in Scheme 1, the reaction requires two steps. First,
R
R
S
N
O
H2N-(CH2)n-PO3H2
HS
CO2Me
Ar
Ar
N (CH )nPO3H2
2
Ar
H
NEt3, MeOH
n = 1, 2, 3
O
(CH2)nPO3H2
1 a-f
R = H, Me
Scheme 1
we have generated the imine from the aminoalkylphosphonic acid (1 eq.) in methanol
as solvent and in the presence of triethylamine (3 eq.). This stage required 1–2 h. Then,
methyl mercaptoacetate was added, and the mixture was stirred for a period of 12–48 h.
The resulting thiazolidinonephosphonic acids 1a–c were isolated after a simple workup
(Table I).
Similarly, thiazolidinonephosphonic acids 1d–f (diastereoisomers mixtures)
were prepared from methyl 2-mercaptopropionate; however, the trials with methyl
2-mercapto-2-methylpropionate failed, and the starting aminoacids were recovered. The
same failure result was observed when we used methyl mercaptoacetate and 1-amino-1-
methylethylphosphonic acid or 1-aminocyclohexylphosphonic acid as a substrate. Thus, it
Table I Synthesis of ω-(2-aryl-4-oxothiazolidin-3-yl)alkylphosphonic acids 1a–f
Imine formation
conditions
Addition
Isolated
Entry
a
(CH2)n
CH2
R
conditions Product yield (%) Mp (◦C)
H
rt, 1 h
rt, 12 h
rt, 24 h
1a
50
191–194
b
c
(CH2)2
(CH2)3
H
H
rt, 3 h
1b
1c
41
73
178–181
137–139
50◦C, 1.5 h
50◦C, 1.5 h/rt,
12 h
d
e
CH2
CH3 rt, 1 h
CH3 rt, 1h
rt, 48 h
rt, 12 h
1d
1e
61
49
182–187
172–175
(CH2)2
f
(CH2)3
CH3 50◦C, 1h
50◦C, 4 h/rt,
12 h
1f
67
136–141

ω-(2-ARYL-4-OXOTHIAZOLIDIN-3-YL)ALKYLPHOSPHONIC ACIDS
2235
is probably that the steric hindrance both in the mercaptoester and in the aminophosphonic
acid limits the scope of the method.
The final 4-thiazolidine phosphonic acids are stable compounds and can be stored at
room temperature for months without decomposition. Their structure was confirmed by IR,
NMR, and elemental or HRMS analysis.
In summary, the protocol described in this article provides a new and simple ac-
cess to ω-(2-aryl-4-oxothiazolidin-3-yl)alkylphosphonic acids directly from easily avail-
able aminophosphonic acids, aromatic aldehydes, and mercaptoacetic esters. The reaction
gives moderate to good yields and avoids a hydrolysis step, which is necessary during the
preparation of such class of compounds.14
EXPERIMENTAL
Melting points are uncorrected. NMR spectra were obtained with a Bruker Avance
III 600, a Varian Gemini 200, and a Tesla BS 687 spectrometer operating at 200 and 80
MHz, respectively, for 1H (TMS); at 151, 50, and 20 MHz for 13C; and at 243 and 80 MHz
for 31P (H3PO4). IR spectra were measured on a Specord 75 instrument and are reported
in cm−1. HRMS (EI, 70 eV) spectra were recorded on a Finnigan MAT 95 instrument. The
elemental analyses were performed by the Laboratory of Microanalysis of the Centre of
Molecular and Macromolecular Studies, Polish Academy of Science in Ło´dz´.
ω-(2-Aryl-4-oxothiazolidin-3-yl)alkylphosphonic Acids 1a–f:
General Procedure
To a suspension of primary aminophosphonic acid (10 mmol) in MeOH (100 mL),
NEt3 (3.00 g, 30 mmol, Table I, entries b–f; 4.00 g, 40 mmol, entry a) was added, and
the mixture was stirred at rt for 20 min. Next, the aromatic aldehyde (10 mmol) was
added, and stirring was continued (temperature and time given in Table I). To the clear
solution thus obtained, methyl mecaptoacetate (1.06 g, 10 mmol, entries a–c) or methyl
2-mercaptopropionate (1.20 g, 10 mmol, entries d–f) was added, and stirring was continued
(temperature and time given in Table I). Then the solvent was evaporated, and the residue
was washed with Et2O (3 × 50 mL, entries a–c, e, f). The residue thus obtained was worked
up in different ways:
2-(4-Oxo-3-phosphonomethylthiazolidin-2-yl)benzoic Acid (1a)
The residue was dissolved in water (30 mL) and acidified with HCl (aq) solution (4
1
mol/dm3, 8.5 mL). The product precipitated as colorless crystals. H NMR (D2O/NaOD,
200 MHz): δ = 2.77 (dd, 2JHA-HM = 15.4 Hz, 2JPH = 9.5 Hz, 1H, PCHAHM), 3.63 (dAB,
5
2
2JHA-HB = 15.9 Hz, JPH = 2.4 Hz, 1H, SCHAHB), 3.74 (AB, JHA-HB = 15.9 Hz, 1H,
SCHAHB), 3.96 (dd, 2JHA-HM = 15.4 Hz, 2JPH = 13.3 Hz, 1H, PCHAHM), 6.47 (s, 1H, CH),
7.06–7.59 (m, 4H, CHarom). 13C NMR (D2O/NaOD, 50 MHz): δ = 34.0 (C-5), 45.1 (d,
1JPC = 137.5 Hz, CH2), 64.3 (C-2), 126.2 (CHarom), 130.9 (CHarom), 131.6 (CHarom), 132.8
(CHarom), 139.4 (Cqarom), 140.4 (Cqarom), 176.6 (d, 3JPC = 2.2 Hz, C-4), 178.8 (COOH). 31
P
NMR (D2O/NaOD, 80 MHz): δ = 12.9. IR (KBr): 3397–2573 (OH), 1663 (C O), 1279
(P O), 1025 (P O). Anal. Calcd for C11H12NO6PS · H2O: C, 39.41; H, 4.21%. Found:
C, 39.85; H, 4.39%.

2236
D. CAL
2-[4-Oxo-2-(thiophen-2-yl)thiazolidin-3-yl]ethylphosphonic Acid (1b)
The residue was dissolved in water (30 mL), charcoal was added, and the mixture
stirred at rt for 1 h. The mixture was filtered, and the filtrate was acidified with HCl (aq)
1
solution (4 mol/dm3, 6.3 mL). The product precipitated as colorless crystals. H NMR
(D2O/NaOD, 80 MHz): δ = 1.28–2.24 (m, 2H, CH2P), 2.94–4.12 (m, 4H, CH2N + CH2S),
6.30 (s, 1H, CH), 7.05–7.68 (m, 3H, CHarom). 13C NMR (D2O/NaOD, 50 MHz): δ = 28.0
1
(d, JPC = 130.1 Hz, CH2), 35.3 (C-5), 41.2 (CH2N), 61.8 (C-2), 129.8 (CHarom), 130.7
(CHarom), 131.0 (CHarom), 145.6 (Cqarom), 174.9 (C-4). 31P NMR (D2O/NaOD, 80 MHz): δ
= 16.6. IR (KBr): 3425–2273 (OH), 1640 (C O), 1198 (P O), 1000 (P O). HRMS (EI)
Calcd for C9H12NO4PS2: 292.9945. Found: 292.9947.
3-[4-Oxo-2-(3-tolyl)thiazolidin-3-yl]propylphosphonic Acid (1c)
The residue was dissolved in MeOH (5 mL) and NaOMe/MeOH solution (1 mol/dm3,
24 mL) was added. Then the solvent was evaporated. The residue was dissolved in water
(30 mL), acidified with HCl (aq) solution (4 mol/dm3, 6.3 mL) and extracted with ethyl
acetate (3 × 30 mL). The organic phase was evaporated and the residue was crystallized
from water to give the product as colorless crystals. 1H NMR (D2O/NaOD, 80 MHz): δ =
1.04–1.97 (m, 4H, 2CH2), 2.29 (s, 3H, CH3), 2.47–2.92 (m, 1H, CH2N), 3.42–3.90 (m, 3H,
CH2N + CH2S), 5.93 (s, 1H, CH), 7.11–7.45 (m, 4H, CHarom). 13C NMR (D2O/NaOD, 20
2
1
MHz): δ = 22.0 (CH3), 22.9 (d, JPC = 3.7 Hz, CH2), 27.7 (d, JPC = 130.7 Hz, CH2),
34.2 (C-5), 45.8 (d,3JPC = 20.7 Hz, CH2), 65.1 (C-2), 125.7 (CHarom), 129.1 (CHarom),
130.7 (CHarom), 131.6 (CHarom), 140.8 (Cqarom), 141.0 (Cqarom), 175.5 (C-4). 31P NMR
(D2O/NaOD, 80 MHz): δ = 19.9. IR (KBr): 3431–2287 (OH), 1647 (C O), 1179 (P O),
1006 (P O). HRMS (EI) Calcd for C13H18NO4PS: 315.0694. Found: 315.0695.
[2-(4-Methoxyphenyl)-5-methyl-4-oxothiazolidin-3-yl]methylphosphonic
Acid (1d)
The residue was mixed with HCl (aq) solution (1 mol/dm3, 28 mL) and the resulting
precipitate washed with acetone/Et2O (1/4, 5 mL) to give the product as colorless crystals.
1H NMR (D2O/NaOD, 80 MHz): δ = 1.46 (d, 3JHH = 7.1 Hz, 3H, CH3), 2.56 (dd, 2JHA-HM
2
= 15.1 Hz, JPH = 9.3 Hz, 1H, PCHAHM), 3.67–3.81 (m, 3H, OCH3 + 1H, PCHAHM),
4.05 (dq, 3JHH = 6.9 Hz, 5JPH = 2.2 Hz, 1H, CHCO), 6.09 (s, 1H, CHN), 6.87–7.22 (m, 4H,
CHarom). 13C NMR (D2O/NaOD, 151 MHz): δ = 18.8 (CH3, minor), 20.0 (CH3, major),
1
1
41.3 (C-5, minor), 41.4 (d, JPC = 147.9 Hz, CH2P, minor), 41.5 (d, JPC = 141.9 Hz,
CH2P, major), 42.2 (C-5, major), 5.6 (OCH3, major + minor), 61.5 (C-2, minor), 61.7 (C-
2, major), 114.7 (CHarom, major + minor), 128.3 (CHarom, minor), 128.8 (CHarom, major),
131.5 (Cqarom, major), 131.8 (Cqarom, minor), 159.5 (Cqarom, major + minor), 175.5 (d,
3JPC = 1.5 Hz, C-4, major), 175.6 (d, 3JPC = 1.5 Hz, C-4, minor). 31P NMR (D2O/NaOD,
243 MHz): δ = 13.2, 13.1 (93:7). IR (KBr): 3423–2325 (OH), 1660 (C O), 1253 (P O),
1012 (P O). HRMS (EI) Calcd for C12H16NO5PS: 317.0487. Found: 317.0497.
2-(5-Methyl-4-oxo-2-phenylthiazolidin-3-yl)ethylphosphonic Acid (1e)
The residue was dissolved in MeOH (5 mL) and NaOMe/MeOH solution (1 mol/dm3,
24 mL) was added. Then the solvent was evaporated. The residue was dissolved in MeOH
(30 mL), acidified with HCl/MeOH (4 mol/dm3, 6.4 mL) and evaporated. The residue thus

ω-(2-ARYL-4-OXOTHIAZOLIDIN-3-YL)ALKYLPHOSPHONIC ACIDS
2237
obtained was dissolved in EtOH (20 mL) and filtered. The filtrate was evaporated, and the
residue was crystallized from ethyl acetate. The product was obtained as colorless crystals.
1H NMR (D2O/NaOD, 80 MHz): δ = 1.22–2.08 (m, 5H, CH3 + CH2P), 2.81–3.26 (m, 1H,
CH2P), 3.57–4.33 (m, 2H, CH2P + CHCO), 5.97 (s, 1H, CHN), 7.51 (s, 5H, CHarom). 13
C
=
NMR (D2O/NaOD, 50 MHz): δ = 21.2 (CH3, minor), 22.3 (CH3, major), 29.1 (d, 1JPC
124.5 Hz, CH2P, major), 29.4 (d, 1JPC = 124.5 Hz, CH2P, minor), 42.9 (CH2N, minor +
major), 44.2 (C-5, minor), 45.0 (C-5, major), 64.0 (C-2, minor), 64.4 (C-2, major), 129.4
(CHarom, minor), 129.9 (CHarom, major), 131.7 (CHarom, major), 131.8 (CHarom, major +
minor), 141.3 (Cqarom, major), 141.8 (Cqarom, minor), 178.6 (C-4, major + minor). 31P
NMR (D2O/NaOD, 80 MHz): δ = 15.71, 15.74 (1:2). IR (KBr): 3439–2303 (OH), 1679
(C O), 1255 (P O), 1000 (P O). HRMS (EI) Calcd for C12H16NO4PS: 301.0538. Found:
301.0537.
3-[2-(4-Chlorophenyl)-5-methyl-4-oxothiazolidin-3-yl]propylphosphonic
Acid (1f)
The residue was dissolved in MeOH (5 mL), and NaOMe/MeOH solution (1 mol/dm3,
24 mL) was added. Then the solvent was evaporated. The residue was acidified with HCl
1
(aq) solution (4 mol/dm3, 6.3 mL) and the product was obtained as colorless crystals. H
NMR (D2O/NaOD, 80 MHz): δ = 1.16–1.88 (m, 7H, CH3 + CH2CH2P), 2.60–2.92 (m, 1H,
CH2P), 3.48–3.84 (m, 1H, CH2P), 4.12 (q, 3JHH = 7.1 Hz, 1H, CHCO), 5.91 (s, 1H, CHN),
7.25–7.90 (m, 4H, CHarom). 13C NMR (D2O/NaOD, 50 MHz): δ = 21.6 (CH3, minor),
1
22.2 (CH3, major), 23.7 (CH2, major + minor), 28.6 (d, JPC = 130.7 Hz, CH2P, major
3
+ minor), 44.3 (C-5, minor), 44.8 (C-5, major), 46.8 (d, JPC = 20.8 Hz, CH2N, major
+ minor), 63.2 (C-2, minor), 63.5 (C-2, major), 130,9 (2CHarom, minor), 131.6 (2CHarom
,
,
major), 136.6 (Cqarom, minor), 136.8 (Cqarom, major), 139.7 (Cqarom, major), 140.0 (Cqarom
minor), 178.6 (C-4, minor + major). 31P NMR (D2O/NaOD, 80 MHz): δ = 19.80, 19.82
(1:3). IR (KBr): 3442–2343 (OH), 1637 (C O), 1181 (P O), 1015 (P O). HRMS (EI)
Calcd for C13H17ClNO4PS: 349.0304. Found: 349.0289.
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