The first one-pot, solvent-free microwave-accelerated, three- componentsynthesis of spirothiazolidin-4-ones via Staudinger/aza-Wittig coupling/cyclization

Article abstract of DOI:10.1002/hlca.201100441

An efficient and rapid, solvent-free, microwave-accelerated, one-pot, three-component protocol for the synthesis of spirothiazolidin-4-ones from organic azides is reported for the first time via Staudinger/aza-Wittig coupling/cyclization. The solvent-free

Full text of DOI:10.1002/hlca.201100441

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Helvetica Chimica Acta – Vol. 95 (2012)
The First One-Pot, Solvent-Free, Microwave-Accelerated, Three-Component
Synthesis of Spirothiazolidin-4-ones via Staudinger/Aza-Wittig Coupling/
Cyclization
by Alagusundaram Ponnuswamy*, Poovan Shanmugavelan, Sangaraiah Nagarajan, and
Murugan Sathishkumar
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai- 625 021,
Tamilnadu, India
(phone: þ 919600868323; e-mail: ramradkrish@yahoo.co.in)
An efficient and rapid, solvent-free, microwave-accelerated, one-pot, three-component protocol for
the synthesis of spirothiazolidin-4-ones from organic azides is reported for the first time via Staudinger/
aza-Wittig coupling/cyclization. The solvent-free approach overcomes the limitations associated with the
prevailing solution-phase methodologies in the case of amines. In particular, its novelty is that it
eradicates the vital limitation, i.e., the accumulation of H2O (by-product), which is known to affect the
yield and rate of the reaction, thus affording the spirothiazolidin-4-ones in short reaction times in
excellent yields.
Introduction. – Spirocyclic compounds are of recent interest due to their interesting
bioactivity profiles [1 – 4]. On the other hand, syntheses of spirothiazolidinones have
received interest and attention from a large number of organic chemists, pharmacol-
ogists, and biologists, due to their significant biological activities associated with the
thiazolidinone nucleus [5]. Consequently, focus is directed towards the development of
elegant and environmentally friendly protocols for the synthesis of spirothiazolidi-
nones.
Of the most frequently used methodologies for the synthesis of spirothiazolidin-4-
ones, the well-documented solution-phase protocol [6 – 10], involves the three-
component reactions of an amine, a ketone, and 2-sulfanylacetic acid, wherein
condensation of the amine with the ketone affords the imine, which reacts with 2-
sulfanylacetic acid to give the desired product. The solution-phase methodologies are
not environmentally benign as they are associated with the hazards due to the organic
solvents. The vital drawback in the solution phase protocol of the synthesis of
thiazolidin-4-ones is the accumulation of H2O (formed as by-product), which is known
to affect the rate of the reaction and yield of the product; hence, the azeotropic removal
of H2O is required.
Thus, the azeotropic removal of H2O has been reported to be crucial for obtaining
high yields of thiazolidin-4-ones starting from amines. Alternatively, desiccants such as
molecular sieves, anhydrous ZnCl2 [11], Na2SO4 [12], N,N-dicyclohexylcarbodiimide
(DCC) [6], or 2-(1H-benzotriazoyl)-1,1,3,3-tetramethyl uronium hexafluorophospate
(HBTU) [13] have been used to accelerate the reaction. Additionally, use of
condensation agents [6][14], microwave irradiation [15], Lewis acids or bases [9],
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
923
and ionic liquids [16] had resulted in improved yields of thiazolidin-4-ones.
Consequently, search for a protocol, which would overcome the above mentioned
limitations, is desirable.
Results and Discussion. – It was planned to elaborate an environmentally friendly
solvent-free synthesis of spirothiazolidin-4-ones via Staudinger/aza-Wittig reaction,
which is known to be a powerful tool in synthetic strategies towards N-containing
heterocycles [17], wherein azides are used as nitrogen source instead of amines. So far,
no report is known involving azides as starting material towards the synthesis of
spirothiazolidin-4-ones.
Recently, we have also reported the advantages of switching from a solution-phase
to a solvent-free methodology to achieve efficient and rapid syntheses of amides [18],
thioamides [19], and cyclic imides [20] under solvent-free conditions. In continuation of
this, we attempted at the three-component synthesis of spirothiazolidin-4-ones under
solvent-free conditions, which would decrease the accumulation of H2O (eliminated
during the course of the reaction) in two ways viz. i) no azeotrope formation and ii) the
microwave heating resulting in spontaneous vaporization of H2O.
At the outset, the one-pot, three-component synthesis of spirothiazolidin-4-one was
attempted (Scheme 1) in various solvents and under solvent-free conditions. A mixture
of (azidomethyl)benzene (1a; 1 equiv.), Ph3P (1.1 equiv.), cyclohexanone (2a;
1.0 equiv.), and 2-sulfanylacetic acid (3; 1.1 equiv.) was heated to reflux in various
solvents, which took around 3 – 7 h (Table 1, Entries 1 – 5) for completion to afford 60 –
84% of spirothiazolidin-4-one 4a.
Scheme 1. Synthesis of Spirothiazolidin-4-one 4a
Table 1. Optimization for the Synthesis of Spirothiazolidin-4-one 4a
Entry
Solvent
Reaction conditions
Time [h]
Yielda) [%]
1
2
3
4
5
6
THF
MeCN
Benzene
Toluene
Xylene
7
6
6
4
60
72
80
82
84
96
3
Solvent-free
15 minb)
a) Yield of isolated product. b) Microwave irradiation (1508, 80 W).
From solvent screening, it is evident that in high-boiling solvents with relatively low
polarity, viz. toluene and xylene (Table 1, Entries 4 and 5), the reaction was rapid and
completed within 3 – 4 h. Based on this, it was envisaged that higher reaction

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Helvetica Chimica Acta – Vol. 95 (2012)
temperatures could be obtained in absence of solvent, and the reaction rate may be
further accelerated by using microwave irradiation. Indeed, under microwave-assisted
solvent-free condition resulted in a prominent increase in the rate of the reaction and
4a was obtained in an excellent yield (96%) in just 15 min (Table 1, Entry 6).
Having optimized the reaction conditions, this convenient synthesis was used to
prepare a library of compounds 4 (Scheme 2). The synthesis involves the in situ
formation of imines via aza-Wittig reaction of nascent phosphazenes with cyclic ketones
2, followed by the instantaneous reaction of the imine with 2-sulfanylacetic acid (3) to
afford 4a – 4l in excellent yields (92 – 96%; Table 21).
Scheme 2. Synthesis of Spirothiazolidin-4-ones 4
The synthesized spirothiazolidin-4-ones 4a – 4l were characterized by IR, NMR (1D
1
and 2D), and mass-spectral techniques. The H-NMR spectrum of the representative
compound 4d showed a singlet at 4.62 ppm for two benzylic H-atoms (NCH2Ph), and a
singlet at 3.67 ppm for the SCH2 and a multiplet at ca. 2.40 ppm for a CH group. In the
13C-NMR spectrum of 4d, the signal of a C¼O group appeared at 171.7 ppm, those of
two CH2 C-atoms appeared at 45.2 ppm (NCH2) and 31.3 ppm (SCH2), respectively,
four CH2 groups absorbed at 30.9 and 38.3 ppm, and the signals of the CH group and of
the quaternary C-atom appeared at 38.3 and 73.7 ppm, respectively. The IR spectrum
showed the C¼O band at 1662 cmꢀ1, and the HR-MS spectrum of 4d exhibited the
[M þ H]þ peak at m/z 338.1512.
Conclusions. – In conclusion, we have described the solvent-free synthesis of
spirothiazolidin-4-ones by a microwave-accelerated, one-pot, three-component strat-
egy via Staudinger/aza-Wittig coupling/cyclization, which is efficient, rapid, and
environmentally benign. This protocol overcomes most of the limitations associated
with the solution-phase methods.
The authors thank IRHPA, DST, for providing 300-MHz NMR instrument for recording the NMR
spectra, and UGC for financial support.
Experimental Part
General. All chemicals and solvents were of commercially high-purity grade purchased from Avra
Synthesis Pvt. Ltd. and Merck Pvt. Ltd., India. The org. solvents used in this study were dried over
appropriate drying agents and distilled prior to use. Column chromatography (CC): SiO2 (60 – 120 mesh).
1H- and 13C-NMR spectra: in CDCl3 on a Bruker Avance 300 spectrometer; the chemical shifts (d) in ppm
For R1, see Table 2.
1
)

Helvetica Chimica Acta – Vol. 95 (2012)
925
Table 2. Microwave-Accelerated, Solvent-Free Synthesis of the Spirothiazolidin-4-ones 4a – 4l
Entry Azido
compound
Ketone
Spirothiazolidin-4-ones
MW-Irradiation
Temp. Time Yielda)
[8]
[min] [%]
1
1a
Cyclohexanone (2a)
4a [6]
150
10
96
2
1b
1c
2a
2a
4b
4c
150
150
15
96
3
4
20
20
96
95
1a
1b
1c
4-Phenylcyclohexanone (2b)
4d
4e
4f
160
160
160
5
6
2b
2b
20
20
94
95
7
8
1a
1b
4-(tert-Butyl)cyclohexanone (2c) 4g
140
140
10
10
95
95
2c
4h

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Helvetica Chimica Acta – Vol. 95 (2012)
Table 2 (cont.)
Entry Azido
Ketone
Spirothiazolidin-4-ones
MW-Irradiation
compound
Temp. Time Yielda)
[8]
[min] [%]
9
1c
2c
4i
140
10
93
10
11
1b
1c
3-Methylcyclohexanone (2d) 4j
160
160
20
20
94
94
2d
4k
12
1a
Cyclopentanone (2e)
4l [21]
150
15
92
a) Yield of the isolated product.
rel. to TMS, J in Hz; 13C-NMR data with respect to the solvent peak (d (CDCl3), 77.0 ppm) as the internal
standard. HR-MS: Bruker Maxis instrument.
Preparation of Organic Azides. Azido compounds 1a [22], 1b [23], and 1c [24] were prepared
according to the previously reported procedures.
General Procedure for the Synthesis of Spirothiazolidin-4-ones 4a – 4l. To a well ground intimate
mixture of Ph3P (1.1 equiv.) and ketone 2 (1.0 equiv.) in a microwave vial (10 ml), equipped with a
magnetic stirring bar, the azido compound 1 (0.2 g, 1.0 equiv.) was added dropwise while stirring. Stirring
was continued until liberation of N2 ceased, and 2-sulfanylacetic acid (3; 1.1 equiv.) was added to the
above mixture, and the reaction vessel was sealed with a septum. It was then placed into the cavity of a
focused monomode microwave reactor (CEM Discover Bench Mate) and operated at 120 – 1408 (temp.
monitored by a built-in IR sensor); power, 80 W for 10 – 20 min. The reaction temp. was maintained by
modulating the power level of the reactor. Then, the mixture was allowed to stand at r.t., and the residue
was purified by CC (SiO2; petroleum ether/AcOEt 97:3) to afford 4a – 4l in 92 – 96% yield. Compounds
4a [6] and 4l [21] are known.
Methyl 2-(3-Oxo-1-thia-4-azaspiro[4.5]dec-4-yl)acetate (4b). Yield: 0.40 g (96%). Gummy matter.
IR (KBr): 1751 (OꢀC¼O), 1683 (NꢀC¼O). 1H-NMR (300 MHz, CDCl3): 1.18 – 1.96 (m, 10 H); 3.50 (s,
2 H); 3.67 (s, 3 H); 3.96 (s, 2 H). 13C-NMR (75 MHz, CDCl3): 171.3; 168.8; 73.0; 52.2; 42.8; 38.0; 30.8;
24.3; 23.1. HR-MS: 244.0935 ([M þ H]þ, C11H18NO3Sþ; calc. 244.0912).
Ethyl 2-(3-Oxo-1-thia-4-azaspiro[4.5]dec-4-yl)acetate (4c). Yield: 0.38 g (96%). Gummy matter. IR
(KBr): 1751 (OꢀC¼O), 1693 (NꢀC¼O). 1H-NMR (300 MHz, CDCl3): 1.23 (t, J ¼ 6.9, 3 H); 1.53 – 1.87
(m, 10 H); 3.96 (s, 2 H); 3.52 (s, 2 H); 4.14 (q, J ¼ 6.9, 2 H). 13C-NMR (75 MHz, CDCl3): 171.4; 168.3;
73.1; 61.4; 43.0; 38.0; 30.8; 24.3; 23.1; 14.0. HR-MS: 258.1097 ([M þ H]þ, C12H20NO3Sþ; calc. 258.1086).

Helvetica Chimica Acta – Vol. 95 (2012)
927
4-Benzyl-8-phenyl-1-thia-4-azaspiro[4.5]decan-3-one (4d). Yield: 0.48 g (95%). White solid. M.p.
1
130 – 1318. IR (KBr): 1662 (NꢀC¼O). H-NMR (300 MHz, CDCl3): 1.94 – 2.03 (m, 8 H); 3.67 (s, 2 H);
2.30 – 2.55 (m, 1 H); 4.62 (s, 2 H); 7.12 – 7.30 (m, 10 H). 13C-NMR (75 MHz, CDCl3): 171.7; 145.5; 137.9;
128.5; 128.4; 127.3; 127.0; 126.6; 126.3; 73.7; 45.2; 42.6; 38.3; 31.3; 30.9. HR-MS: 338.1512 ([M þ H]þ,
C21H24NOSþ; calc. 338.1500).
Methyl 2-(3-Oxo-8-phenyl-1-thia-4-azaspiro[4.5]dec-4-yl)acetate (4e). Yield: 0.52 g (94%). White
solid. M.p. 160 – 1618. IR (KBr): 1765 (OꢀC¼O), 1683 (NꢀC¼O). 1H-NMR (300 MHz, CDCl3): 1.85 –
2.02 (m, 8 H); 3.63 (s, 2 H); 2.35 – 2.55 (m, 1 H); 3.77 (s, 3 H); 4.08 (s, 2 H); 7.22 – 7.33 (m, 5 H).
13C-NMR (75 MHz, CDCl3): 171.4; 168.9; 145.3; 128.4; 126.6; 126.4; 72.5; 52.4; 42.9; 42.6; 38.1; 31.0; 30.7.
HR-MS: 320.1221 ([M þ H]þ, C17H28NOSþ; calc. 320.1242).
Ethyl 2-(3-Oxo-8-phenyl-1-thia-4-azaspiro[4.5]dec-4-yl)acetate (4f). Yield: 0.46 g (95%). White
solid. M.p. 109 – 1108. IR (KBr): 1762 (OꢀC¼O), 1677 (NꢀC¼O). 1H-NMR (300 MHz, CDCl3): 1.29 (t,
J ¼ 6.9, 3 H); 1.85 – 2.02 (m, 8 H); 2.35 – 2.65 (m, 1 H); 3.63 (s, 2 H); 4.06 (s, 2 H); 4.14 (q, J ¼ 6.9, 2 H);
7.22 – 7.35 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 171.4; 168.4; 145.4; 128.5; 126.7; 126.4; 72.6; 61.6; 43.1;
42.6; 38.2; 31.0; 30.8; 14.1. HR-MS: 334.1409 ([M þ H]þ, C18H24NO3Sþ; calc. 334.1399).
4-Benzyl-8-(tert-butyl)-1-thia-4-azaspiro[4.5]decan-3-one (4g). Yield: 0.53 g (95%). Gummy mat-
ter. IR (KBr): 1660 (NꢀC¼O). 1H-NMR (300 MHz, CDCl3): 0.83 (s, 9 H); 1.32 – 1.80 (m, 8 H); 3.62 (s,
2 H); 4.56 (s, 2 H); 7.26 – 7.33 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 171.8; 138.0; 128.5; 127.2; 127.0;
74.3; 46.6; 45.1; 38.4; 32.2; 31.3; 27.4; 24.3. HR-MS: 318.1842 ([M þ H]þ, C19H22NOSþ; calc. 318.1813).
Methyl 2-[8-(tert-Butyl)-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl]acetate (4h). Yield: 0.49 g (95%).
Gummy matter. IR (KBr): 1762 (OꢀC¼O), 1677 (NꢀC¼O). 1H-NMR (300 MHz, CDCl3): 0.86 (s,
9 H); 1.25 – 1.96 (m, 9 H); 3.58 (s, 2 H); 3.75 (s, 3 H); 4.02 (s, 2 H). 13C-NMR (75 MHz, CDCl3): 171.5;
169.0; 73.1; 52.4; 46.6; 42.9; 38.3; 32.3; 31.0; 27.5; 24.2. HR-MS: 300.1572 ([M þ H]þ, C15H26NO3Sþ; calc.
300.1555).
Ethyl 2-[8-(tert-Butyl)-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl]acetate (4i). Yield: 0.39 g (93%). Gum-
my matter. IR (KBr): 1760 (OꢀC¼O), 1671 (NꢀC¼O). 1H-NMR (300 MHz, CDCl3): 0.87 (s, 9 H); 1.28
(t, J ¼ 7.2, 3 H); 1.33 – 1.97 (m, 8 H); 3.58 (s, 2 H); 4.00 (s, 2 H); 4.20 (q, J ¼ 7.2, 2 H). 13C-NMR
(75 MHz, CDCl3): 171.4; 168.3; 73.1; 61.3; 46.4; 42.9; 38.2; 32.1; 30.8; 27.3; 24.0; 14.0. HR-MS: 314.1728
([M þ H]þ, C16H28NO3Sþ; calc. 314.1712).
Methyl 2-(7-Methyl-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)acetate (4j). Yield: 0.42 g (94%). Gummy
matter. IR (KBr): 1760 (OꢀC¼O), 1665 (NꢀC¼O). 1H-NMR (300 MHz, CDCl3): 0.94 (d, J ¼ 6.3, 3 H);
1.25 – 1.90 (m, 9 H); 3.58 (s, 2 H); 3.75 (s, 3 H); 4.02 (s, 2 H). 13C-NMR (75 MHz, CDCl3): 171.4; 168.9;
73.1; 52.3; 46.3; 42.8; 37.5; 33.2; 30.2; 29.8; 22.7; 22.0. HR-MS: 258.1121 ([M þ H]þ, C12H20NO3Sþ; calc.
258.1086).
Ethyl 2-(7-Methyl-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)acetate (4k). Yield: 0.35 g (94%). Gummy
matter. IR (KBr): 1768 (OꢀC¼O), 1663 (NꢀC¼O). 1H-NMR (300 MHz, CDCl3): 0.93 (d, J ¼ 6.6, 3 H);
1.28 (t, J ¼ 6.9, 3 H); 1.59 – 1.90 (m, 9 H); 3.58 (s, 2 H); 4.00 (s, 2 H); 4.20 (q, J ¼ 6.9, 2 H). 13C-NMR
(75 MHz, CDCl3): 171.1; 168.1; 72.9; 61.1; 46.1; 42.8; 37.3; 32.1; 30.9; 27.3; 22.5; 21.8; 13.8. HR-MS:
272.1228 ([M þ H]þ, C13H22NO3Sþ; calc. 272.1242).
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Received November 12, 2011