Ultrasound-mediated willgerodt-kindler reactions: Non-thermal synthesis of thioacetamides

Article abstract of DOI:10.1080/10426507.2010.550269

Non-thermal, solvent-free condensation of several aryl methyl ketones with amines and elemental sulfur is efficiently conducted using ultrasonic irradiation within short time periods. Consequently, various thioacetamides are conveniently synthesized. Simi

Full text of DOI:10.1080/10426507.2010.550269

This article was downloaded by: [University of Waterloo]
On: 11 October 2014, At: 11:55
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
Ultrasound-Mediated Willgerodt–Kindler
Reactions: Non-thermal Synthesis of
Thioacetamides
Mohammad M. Mojtahedi a , Tooba Alishiri a & M. Saeed Abaee a
a Chemistry and Chemical Engineering Research Center of Iran , P.O.
Box 14335-186, Tehran, Iran
Published online: 24 Aug 2011.
To cite this article: Mohammad M. Mojtahedi , Tooba Alishiri & M. Saeed Abaee (2011) Ultrasound-
Mediated Willgerodt–Kindler Reactions: Non-thermal Synthesis of Thioacetamides, Phosphorus, Sulfur,
and Silicon and the Related Elements, 186:9, 1910-1915, DOI: 10.1080/10426507.2010.550269
To link to this article: http://dx.doi.org/10.1080/10426507.2010.550269
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Phosphorus, Sulfur, and Silicon, 186:1910–1915, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.550269
ULTRASOUND-MEDIATED WILLGERODT–KINDLER
REACTIONS: NON-THERMAL SYNTHESIS OF
THIOACETAMIDES
Mohammad M. Mojtahedi, Tooba Alishiri, and M. Saeed Abaee
Chemistry and Chemical Engineering Research Center of Iran,
P.O. Box 14335-186, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract Non-thermal, solvent-free condensation of several aryl methyl ketones with amines
and elemental sulfur is efficiently conducted using ultrasonic irradiation within short time pe-
riods. Consequently, various thioacetamides are conveniently synthesized. Similar experiments
at controlled temperature (25 1◦ C) resulted in comparable yields, showing the promotional
role of ultrasound irradiation in the progress of the reaction.
Keywords Multicomponent; Willgerodt–Kindler reaction; ultrasound irradiation; solvent-free;
thioacetamide
INTRODUCTION
Currently, multicomponent reactions (MCRs)1 are considered as one of the key syn-
thetic strategies in organic chemistry2 since they offer a combination of more than two
reactants in one pot and allow direct access to complex target molecules in a single step.
In this context, oxidative condensation of acetophenone derivatives with elemental sulfur
and amines, known as the Willgerodt–Kindler reaction,3 has served as an important MCR
in synthetic organic chemistry, leading to the formation of phenylthioacetamides, which
are known to possess a variety of biological4 and medicinal5 properties. In addition, the
thioacetamide products are conveniently converted to their corresponding arylacetic acid
derivatives,6 which in fact exhibit a vast range of biological activities7 and are used as key
Received 4 August 2010; accepted 15 December 2010.
Partial financial support by the Ministry of Science, Research, and Technology of Iran is greatly acknowl-
edged.
Address correspondence to Mohammad M. Mojtahedi, Chemistry and Chemical Engineering Research
Center of Iran, P.O. Box 14335-186, Tehran, Iran. E-mail: mojtahedi@ccerci.ac.ir
1910

NON-THERMAL SYNTHESIS OF THIOACETAMIDES
1911
intermediates in the preparation of other synthetic targets.8 The Willgerodt–Kindler reac-
tion traditionally requires high-temperature treatment of the reactants in various solvents.9
Although several modern methods using solvent-free systems,10 ionic liquid media,11 and
microwave irradiation12 are developed in recent years, there is still a demand for proce-
dures capable of conducting the reaction under more environmentally friendly and milder
conditions.
The role of ultrasonic irradiation in boosting the reactivity and selectivity of syn-
thetic organic reactions is widely demonstrated in recent years.13 Consequently, several
protocols are developed to perform chemical reactions in shorter time periods and under
more environmentally benign conditions. Some illustrative instances include the use of
sonochemistry in multi-component procedures,14 synthesis of heterocyclic compounds,15
organometallic chemistry,16 protection of functional groups,17 cycloadditions,18 and ring
opening of epoxides.19 Based on our previous experiences in sonochemistry20 and in con-
tinuation of our attempts to develop green chemical methodologies,21 we now report a
novel procedure for solvent-free Willgerodt–Kindler reactions using ultrasound irradiation
(Scheme 1).
Scheme 1
RESULTS AND DISCUSSION
First, a 1.0:1.2:1.4 mixture of acetophenone, sulfur, and morpholine was sonicated
under various sets of conditions. The best results were obtained in the presence of no solvent,
leading to the formation of 1-morpholino-2-phenylethanethione 2a only after 10 min of
sonication (Table 1, entry 1). The solid product was extracted from the reaction mixture
and recrystallized from diethyl ether. Control experiments showed the crucial role of the
ultrasonic irradiation in the reaction and excluded the effect of a possible simultaneous
thermal activation. In other words, when the same reaction was conducted at a constant
temperature of 25 1◦ C, comparable results were obtained but after 5–6 min of excess
sonication. Alternatively, in the absence of irradiation, no formation of 2a was noticed.
To show the diversity of the method, other derivatives of acetophenone-bearing electron-
releasing (entries 2–5), electron-withdrawing (entries 6–11), and naphthyl substituents
(entry 12) were used. In all cases, the desired products were obtained in good yields. In
addition, the rates of all reactions were relatively high and not much relation between the
activities and the physical specifications of the starting acetophenones could be concluded.
To further study the generality of the method, similar reactions were conducted using
other amines (piperidine and pyrrolidine) and various acetophenone derivatives bearing
different substituents, as shown in Table 2. These reactions led to relatively lower yields of
the respective products within comparable time periods. This lower reactivity to participate
in Willgerodt–Kindler reactions is usual for these amines and has been often observed by
other researchers.24,26,27

1912
M. M. MOJTAHEDI ET AL.
Table 1 Ultrasound-promoted Willgerodt–Kindler reactions with morpholine
Entry
1
Substrate
Product
Time (min)
10
Yield (%)a
82 (Yadav et al., 2007)11
2
3
15
25
75 (Yadav et al., 2007)11
75 (Giordano et al., 2005)5b
4
25
65 (Yadav et al., 2007)11
5
6
15
15
65 (Yadav et al., 2007)11
70 (Harrowven et al., 1999)22
7
8
20
20
82 (Yadav et al., 2007)11
84 (Rolfs and Liebscher, 1994)23
9
20
25
20
80 (Yadav et al., 2007)11
78 (Present work)
10
11
85 (Yadav et al., 2007)11
12
20
75 (Yadav et al., 2007)11
aIsolated yields.

NON-THERMAL SYNTHESIS OF THIOACETAMIDES
1913
Table 2 Ultrasound-promoted Willgerodt–Kindler reactions with other amines
Entry Substrate
1
Product
Time (min)
15
Yield (%)a
55 (Lee et al. 1988)25
2
3
4
20
25
25
40 (Lee et al. 1988)25
52 (Lee et al. 1988)25
54 (Cornea et al. 1980)26
68 (Sundberg et al. 1981)27
5
6
10
15
60 (Rolfs and Liebscher 1994)23
aIsolated yields.
In conclusion, we have reported a facile non-thermal Willgerodt–Kindler reaction
using a sonochemical method. The reactions complete within a few minutes, yields are
relatively high, no solvent or extra additive is required during the course of the reactions,
and the method is environmentally safe. A comparison of the results with some other related
methods is provided in Table 3, where the Willgerodt–Kindler reaction of acetophenone
with morpholine is chosen as a standard reaction to show the advantages of the method. It
could be concluded from the table that the reaction reaches completion within a relatively
short time period as opposed to long-time high-temperature treatment required in thermal
methods.
Table 3 Comparison of the present work with some other related methods for the reaction of acetophenone with
morpholine and sulfur
Entry
Condition
Time
Yield (%)
Reference
1
2
3
4
5
6
7
Ultrasound irradiation
Ionic liquid/110◦C
Reflux
10 min
3 h
20 h
6 h
4 min
2 h
6 h
82
92
66
41
50
90
67
Present work
Yadav et al. (2007)11
Liu et al. (2006)28
p-MeC6H4SO3H/120◦C
Microwave irradiation
Quinoline/123◦C
Giordano et al. (2009)5a
Nooshabadi et al. (1999)12
Carison et al. (1986)9
Poupaert et al. (2004)29
4-Me-morpholine/DMF/135◦C

1914
M. M. MOJTAHEDI ET AL.
EXPERIMENTAL
General
The reactions were monitored by thin-layer chromatography (TLC). Fourier trans-
form infrared (FT-IR) spectra were recorded using KBr disks on a Bruker Vector-22 infrared
spectrometer and absorptions were reported as wave numbers (cm−1). Nuclear magnetic
resonance (NMR) spectra were obtained in CDCl3 solutions on a FT-NMR Bruker Ultra
ShieldTM (500 MHz) instrument and the chemical shifts were expressed as δ units, with
Me4Si as the internal standard. Mass spectra were obtained on a Finnigan Mat 8430 appa-
ratus at an ionization potential of 70 eV. All chemicals and reagents were purchased from
commercial sources and were used without further purification. Sonication was performed
ꢀR
using a Sartorius Ultrasonic-Homogenizer LABSONIC P 230V/50 Hz instrument with a
frequency of 24 KHz and a nominal power of 460 W/cm2. The intensity level of irradiation
was adjusted at the 80% level for the synthesis of the products. In all reactions, the tip of
the sonotrode was located in the same position—just under the liquid surface—in order to
obtain optimal sonication and reproducible results.
Typical Procedure
A mixture containing an acetophenone derivative (2 mmol), sulfur (77 mg, 2.4 mmol),
and morpholine (244 mL, 2.8 mmol) was sonicated in a 10-mL test tube for an appropriate
length of time (as indicated in Table 1) until TLC showed complete disappearance of the
starting materials. In the temperature-controlled experiments, reactions were performed in
a water bath at 25 1◦ C. After completion of the reactions, mixtures were diluted with
diethyl ether and washed with brine. The organic phase was then dried by filtering through
a short column of Na2SO4. The pure products were obtained either by recrystallization (in
ether) or flash column chromatography of the residue (using a 1:4 mixture of EtOAC/hexane
over silica gel). Products were identified based on their melting points and spectral data.
Known structures were verified by comparison of their data with those reported in the
literature.
Spectral Data for the New Compound
2-(4-Iodophenyl)-1-morpholinoethanethione (2j): m.p. 93–94◦ C; IR (KBr, cm−1
)
1
1498, 1109; H NMR (CDCl3) δ 3.48 (t, J = 5 Hz, 2H), 3.65 (t, J = 5 Hz, 2H), 3.78 (t,
J = 5 Hz, 2H), 4.31 (s, 2H), 4.38 (t, J = 5 Hz, 2H), 7.12 (d, J = 8 Hz, 2H), 7.69 (d, J = 8
Hz, 2H); 13C NMR (CDCl3) δ 50.3, 50.5, 51.2, 66.6, 66.8, 92.9, 130.3, 135.9, 138.4, 199.6;
MS m/z (%) 347 (M+, 25), 260 (12), 217 (15), 134 (74), 89 (100); Analysis calculated for
C12H14INOS: C, 41.51; H, 4.06; N, 4.03. Found: C, 41.80; H, 4.09; N, 4.08.
REFERENCES
1. J. Zhu and H. Bienayme, Multicomponent Reactions (Wiley-VCH, Weinheim, 2005).
2. C. O. Kappe, Acc. Chem. Res., 33, 879–888 (2000).
3. E. V. Brown, Synthesis, 358–375 (1975).
4. C. L. Leresque, U.S. Patent, 2,560,296 (1951, July 10).

NON-THERMAL SYNTHESIS OF THIOACETAMIDES
1915
5. (a) A. Giordano, K. K. Vasu, H. M. Thakar, R. S. Giri, S. G. Yerande, G. S. Inamdar, J. C. Kaila,
P. H. Ahmedabad, and V. Sudarsanam, U.S. Patent, 0306,073,A1 (2009, December 10); (b)D. S.
Bose and A. V. Narsaiah, Bioorg. Med. Chem., 13, 627–630 (2005).
6. M. M. Alam and S. R. Adapa, Synth. Commun., 33, 59–63 (2003).
7. G. Tuncel and C. Nergiz, Lett. Appl. Microbiol., 17, 300–302 (1993).
8. (a) M. Pour, M. Spulak, V. Balsanek, J. Kunes, V. Buchta, and K. Waisser, Bioorg. Med. Chem.
Lett., 10, 1893–1895 (2000); (b) F. M. Moghaddam, Z. Mirjafary, H. Saeidian, and M. J. Javan,
Synlett, 892–896 (2008).
9. R. Carison, T. Lundstedt, and R. Shabana, Acta. Chem. Scand. B, 40, 534–544 (1986).
10. K. Aghapoor, H. R. Darabi, and K. Tabar-Heydar, Phosphorus Sulfur Silicon Relat. Elem., 177,
1183–1187 (2002).
11. J. S. Yadav, B. V. S. Reddy, G. Kondaji, J. S. S. Reddy, and K. Nagaiah, J. Mol. Catal. A Chem.,
266, 249–253 (2007).
12. M. Nooshabadi, K. Aghapoor, H. R. Darabi, and M. M. Mojtahedi, Tetrahedron Lett., 40,
7549–7552 (1999).
13. (a) G. Cravotto and P. Cintas, Chem. Soc. Rev., 35, 180–196 (2006); (b) V. V. Dabholkar and F.
Y. Ansari, Phosphorus, Sulfur Silicon Relat. Elem., 185, 298–305 (2010).
14. V. N. Pathak, R. Joshi, J. Sharma, N. Gupta, and V. M. Rao, Phosphorus Sulfur Silicon Relat.
Elem., 184, 1854–1865 (2009).
15. R. Cella and H. A. Stefani, Tetrahedron, 65, 2619–2641 (2009).
16. G. Palmisano, W. Bonrath, L. Boffa, D. Garella, A. Barge, and G. Cravotto, Adv. Synth. Catal.,
349, 2338–2344 (2007).
17. J. Singh, N. Gupta, G. L. Kad, and J. Kaur, Synth. Commun., 36, 2893–2900 (2006).
18. G. Cravotto, V. V. Fokin, D. Garella, A. Binello, L. Boffa, and A. Barge, J. Comb. Chem., 12,
13–15 (2010).
19. A. Kamal, S. F. Adil, and M. Arifuddin, Ultrason. Sonochem., 12, 429–431 (2005).
20. (a) M. M. Mojtahedi, M. R. Saidi, J. S. Shirzi, and M. Bolourtchian, Synth. Commun., 31,
3587–3592 (2001); (b) M. M. Mojtahedi, M. S. Abaee, V. Hamidi, and A. Zolfaghari, Ultrason.
Sonochem., 14, 596–598 (2007); (c) M. S. Abaee, V. Hamidi, and M. M. Mojtahedi, Ultrason.
Sonochem., 15, 823–827 (2008); (d) M. M. Mojtahedi, M. S. Abaee, P. Mahmoodi, and M. Adib,
Synth. Commun., 40, 2067–2074 (2010); (e) M. M. Mojtahedi, M. Javadpour, and M. S. Abaee,
Ultrason. Sonochem., 15, 828–832 (2008).
21. (a) M. M. Mojtahedi, E. Akbarzadeh, R. Sharifi, and M. S. Abaee, Org. Lett., 9, 2791–2793
(2007); (b) M. M. Mojtahedi, H. Abbasi, and M. S. Abaee, J. Mol. Catal. A Chem., 250, 6–8
(2006); (c) M. M. Mojtahedi, M. S. Abaee, M. M. Heravi, and F. K. Behbahani, Monatsh. Chem.,
138, 95–99 (2007).
22. D. C. Harrowven, M. C. Lucas, and P. D. Howes, Tetrahedron, 55, 1187–1196 (1999).
23. A. Rolfs and J. Liebscher, Synthesis, 683–684 (1994).
24. M. F. Kosterina, Y. Y. Morzherin, A. V. Tkachev, T. V. Rybalova, Y. V. Gatilov, and V. A.
Bakulev, Russ. Chem. Bull., 51, 653–658 (2002).
25. V. J. Lee, W. V. Curran, T. F. Fields, and K. Learn, J. Hetrocycl. Chem., 25, 1873–1891 (1988).
26. F. Cornea, C. Cercasov, and M. Ciureanu, Spectrochim. Acta A, 36, 775–782 (1980).
27. R. J. Sundberg, C. P. Walters, and J. D. Bloom, J. Org. Chem., 46, 3730–3732 (1981).
28. W. W. Liu, Y. Q. Zhao, R. B. Xu, L. J. Tang, and H. W. Hu, Chinese J. Chem., 24, 1472–1475
(2006).
29. J. H. Poupaert, S. Duarte, E. Colacino, P. Depreux, C. R. McCurdy, and D. L. Lambert, Phos-
phorus, Sulfur Silicon Relat. Elem., 179, 1959–1973 (2004).