An efficient tandem aldol condensation-thia-Michael addition process

Article abstract of DOI:10.1016/j.tetlet.2012.06.040

An efficient synthesis of β-aryl-β-mercapto ketones is achieved via a tandem aldol condensation-thia-Michael addition process using an aqueous medium and diethylamine. Addition of different thiols to α,β- unsaturated ketones, formed in situ from the condensation of acetophenone derivatives with aldehydes, led to a rapid and high yielding synthesis of the products under very mild conditions using no expensive additive or catalyst. Products which precipitated spontaneously in the reaction mixtures were separated by simple filtration and purified by recrystallization.

Full text of DOI:10.1016/j.tetlet.2012.06.040

Tetrahedron Letters 53 (2012) 4405–4408
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An efficient tandem aldol condensation-thia-Michael addition process
⇑
⇑
M. Saeed Abaee , Somayeh Cheraghi, Somayeh Navidipoor, Mohammad M. Mojtahedi , Soodabeh Forghani
Department of Organic Chemistry and Natural Products, Chemistry and Chemical Engineering Research Center of Iran, Pajouhesh Blvd., 17th Km Tehran-Karaj Highway,
P.O. Box 14335-186, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of b-aryl-b-mercapto ketones is achieved via a tandem aldol condensation-thia-
Received 22 April 2012
Revised 26 May 2012
Accepted 8 June 2012
Available online 17 June 2012
Michael addition process using an aqueous medium and diethylamine. Addition of different thiols to
a,b-unsaturated ketones, formed in situ from the condensation of acetophenone derivatives with alde-
hydes, led to a rapid and high yielding synthesis of the products under very mild conditions using no
expensive additive or catalyst. Products which precipitated spontaneously in the reaction mixtures were
separated by simple filtration and purified by recrystallization.
Keywords:
Tandem
Ó 2012 Elsevier Ltd. All rights reserved.
Aldol condensation
Michael addition
Aqueous medium
The thia-Michael conjugate addition is an important process in
organic chemistry and has versatile applications in biosynthesis1
and in the construction of bioactive compounds.2–4 The process is
an effective route for the synthesis of b-sulfido derivatives,5–7
which are precursors to synthetic equivalents of b-acylvinyl cat-
ions8 and homoenolates.9 Moreover, the thia-Michael addition to
purification of intermediates.19,20 Thus, tandem reactions are
important from operational, economical, and environmental points
of view.21 In continuation of our studies on the development of
environmentally friendly aqueous procedures,22–24 and on the ba-
sis of our studies on aldol condensation reactions,25–27 we herein
report a novel tandem aldol condensation-thia-Michael addition
process using an aqueous medium and Et2NH, which under very
mild conditions results in the efficient synthesis of b-aryl-b-mer-
capto ketones in one-pot from aldehydes, acetophenones, and thi-
ols (Scheme 1). A search of the literature revealed the existence of a
single related example, reported by Kumar and Akanksha on a mul-
ticomponent synthesis of b-aryl-b-mercapto ketones under ZrCl4
catalysis.28 For other closely related approaches, see the investiga-
tions by Wang’s group on enantioselective organocatalyzed tan-
dem Michael–aldol29 and double Michael addition reactions.30
a,b-unsaturated carbonyl compounds provides a practical strategy
for the selective protection of C@C bonds of conjugated enones, be-
cause regeneration of the double bond can be achieved conve-
niently by removal of the sulfur moiety.3,10 In this regard, many
catalytic systems have been developed for the conjugate addition
of thiols to
a,b-unsaturated carbonyl compounds including Lewis
acids,11–13 solid supports,14,15 and ionic liquids.16–18 However, sev-
eral of these systems are limited because of the long reaction
times, relatively harsh conditions, the use of expensive or noncom-
mercial catalysts, and relatively low yields of products. In addition,
the conjugated enones themselves require a separate preparation.
These difficulties call for new methodologies and approaches to
expand the synthetic scope of thia-Michael conjugate addition
chemistry.
O
O
O
H2O
Et2NH
+
H
A tandem process is a sequence of reactions going through reac-
tive intermediates. The process usually leads to the selective for-
mation of products incorporating all of the starting materials and
allows the synthesis of complex organic molecules and libraries
of compounds from simple reactants without the separation and
2a
1a
4aa
Ph SH
3a
Ph
O
S
⇑
Corresponding authors. Tel.: +98 21 44580720; fax: +98 21 44580785.
E-mail addresses: abaee@ccerci.ac.ir (M.S. Abaee), mojtahedi@ccerci.ac.ir (M.M.
4a
Mojtahedi).
Scheme 1. Three-component synthesis of b-aryl-b-mercapto ketones.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.040

4406
M. S. Abaee et al. / Tetrahedron Letters 53 (2012) 4405–4408
Table 1
Initially, we optimized the conditions using the reaction of ace-
Effect of different amines on the synthesis of 4a
tophenone (1a) with benzaldehyde (2a) and thiophenol (3a) at
ambient temperature, as shown in Table 1. When 1a and 2a were
mixed in aqueous Et2NH, TLC showed the maximum formation of
4aa after 3 hours. Addition of 3a to the mixture at this point led
to quantitative consumption of the reactants within a few minutes
and the formation of 4a in 93% yield (entry 1). In the absence of
amine (entry 2) or water (entry 3), the reaction was either halted
completely or proceeded very slowly illustrating the combined
promoting effects of both H2O and Et2NH. Other secondary amines
behaved similarly (entries 4–6), while both primary (entries 6–8)
and tertiary (entries 8–10) amines showed much lower efficiency.
This can be attributed to differences in the basicity and solubility of
amines. All the secondary amines employed have comparably high
basicities and are miscible with water, while the other amines have
lower aqueous solubilities and/or weaker basicities.31
Entry
Conditions
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
H2O/Et2NH
H2O
Et2NH
H2O/pyrrolidine
H2O/piperidine
H2O/DBU
H2O/aniline
H2O/hexylamine
H2O/DABCO
H2O/Et3N
4
10
10
4
4
4
4
4
4
4
93
0
15
85
80
95
5
23
25
49
10
a
GC yields.
Table 2
A study of the effect of additives on the synthesis of 4a
For organic reactions conducted in aqueous media, it is known
that either the repulsive hydrophobic interactions of the reactants
with water,32,33 or hydrogen bonding activation of functional
groups by water,34,35 is responsible for the rate of the reaction.
To shed light on the mechanism of the present process, several par-
allel reactions of 1a with 2a and 3a were conducted, as summa-
rized in Table 2. For a meaningful comparison of the results, the
reactions were stopped before all the reactants had been con-
sumed. Entry 1 shows the results for the reaction conducted under
optimized H2O/Et2NH conditions after 2 hours. In the absence of
water, a dramatic rate decrease was observed which highlights
the crucial role of the aqueous medium (entry 2). The use of NaCl
(entries 3 and 4), LiCl (entries 5 and 6), and KCl (entries 7 and 8)
solutions also reduced the yields of the process. Rate retardation
was clearly observed at higher concentrations of NaCl and LiCl dis-
favoring the ‘salting-out’36,37 effect and excluded hydrophobic
interactions as being the driving force. Conversely, a rate accelera-
tion was seen for the reactions performed in LiClO4 solutions (en-
Entry
Additive
Yielda,b (%)
1
2
3
4
5
6
7
8
9
H2O/Et2NH
Et2NH
40
5
7
NaCl (1.5 M)/Et2NH
NaCl (3.0 M)/Et2NH
LiCl (1.5 M)/Et2NH
LiCl (3.0 M)/Et2NH
KCl (1.5 M)/Et2NH
KCl (3.0 M)/Et2NH
LiClO4 (1.5 M)/Et2NH
LiClO4 (3.0 M)/Et2NH
4
20
12
18
13
61
64
10
a
GC yields.
Reactions were stopped after 2 hours.
b
H OH
O
H
O
O
PhCHO
H
NHEt2
Ph
Ph
Ph
tries
9 and 10). Therefore, a favorable hydrogen-bonded
association of the reactants can be assumed which lowers the en-
ergy profile of the whole process similar to a Lewis acid mediated
reaction (Scheme 2).38–40
To support the proposed mechanism, the reaction was stopped
before the addition of the thiol and after TLC showed complete
consumption of benzaldehyde and acetophenone. Analysis of the
reaction mixture showed the presence of the single product 4aa
in 95% yield. The isolated product was subjected to reaction with
3a under the same conditions and produced a high yield of 4a
within a few minutes.
H OH
Ph
Ph
O
S
O
O
OH
Ph
-H2O
+H2O
Ph
Ph
Ph
Ph
H
NHEt2
Ph SH
Ph S
Scheme 2. A possible mechanistic pathway.
Table 3
Acetophenone derived b-aryl-b-mercapto ketones synthesized under the optimum conditions
Entry
Aldehyde + thiol
Product
Time (h)
3
Yielda (%)
1
PhCHO + 4-MeC6H4SH
95
O
S
4b
Ph
Ph
2
PhCHO + 3-MeOC6H4SH
4
96
O
S
S
OMe
4c
Ph
O
Ph
Ph
Ph
Ph
3
4
PhCHO + PhCH2SH
4
5
98
95
Ph
O
4d
S
PhCHO + 4-MeOC6H4SH
Ph
OMe 4e

M. S. Abaee et al. / Tetrahedron Letters 53 (2012) 4405–4408
4407
Table 3 (continued)
Entry
Aldehyde + thiol
Product
Time (h)
5
Yielda (%)
O
O
O
S
S
5
6
PhCHO + 2-furyl-CH2SH
98
95
4f
Ph
Ph
Ph
C6H5CHO + Me(CH2)4SH
4-MeC6H4CHO + PhSH
5
4
4g
Ph
Ph
O
O
O
S
S
S
7
8
90
96
92
98
Ph
Ph
Ph
4h
Ph
Ph
Ph
4-MeC6H4CHO + PhCH2SH
4-MeOC6H4CHO + PhCH2SH
4-O2NC6H4CHO + PhCH2SH
4
4
5
4i
OMe
NO2
9
4j
O
O
S
S
Ph
Ph
10
4k
11
4-MeOC6H4CHO + Me(CH2)7SH
5
95
4l
OMe
a
Isolated yield.
To show the generality of the process, we applied the conditions
to reactions of 1a with a variety of other aldehydes and thiols (Table
3).41 When mixtures of 1a and 2a were reacted with different thiols
bearing electron-releasing (entry 1) or electron-withdrawing (entry
2) substituents, products 4b and 4c were obtained in high yields,
respectively. Similarly the same reactions with benzylic (entries
3–5) and aliphatic thiols (entry 6) gave high yields of products.
The scope of the procedure was expanded by variation of the
aldehyde component. Various aldehydes with different electronic
characters reacted under the optimized conditions to produce b-
aryl-b-mercapto ketones in high yields (entries 7–10). Finally, to
show the generality of the procedure, we subjected acetophenone
derivatives bearing electron-withdrawing or electron-releasing
groups to the reaction conditions: again high yields of products
were obtained, as shown in Scheme 3.
In summary, a very convenient procedure has been developed
for the synthesis of b-aryl-b-mercapto ketones at ambient temper-
ature. The reactions gave high yields of products in short times. The
generality of the reaction and its efficient combination of two tra-
ditional steps into a one-pot process make it an interesting and
useful addition to present methods. Additional in situ reactions
of chalcone intermediates with other nucleophiles and reactants
are under investigation in our laboratory.
Acknowledgements
Authors would like to thank the Iranian National Science Foun-
dation (INSF-88002449) for financial support of this work.
Supplementary data
O
O
S
Ph
S
Ph
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.040. These data include MOL files and InChiKeys of the most
important compounds described in this article.
Ph
Ph
NO2
I
4m
, 73%
4n
, 83%
References and notes
1. Fujita, E.; Nagao, Y. Bioorg. Chem. 1977, 6, 287–309.
2. Fluharty, A. L. In The Chemistry of Thiol Group; Patai, S., Ed.; Wiley: New York,
1974; p 589.
3. Trost, B. M.; Keeley, D. E. J. Org. Chem. 1975, 40, 2013.
4. Xu, R.; Cole, D.; Asberom, T.; Bara, T.; Bennett, C.; Burnett, D. A.; Clader, J.;
Domalski, M.; Greenlee, W.; Hyde, L.; Josien, H.; Li, H.; McBriar, M.; McKittrick,
B.; McPhail, A. T.; Pissarnitski, D.; Qiang, L.; Rajagopalan, M.; Sasikumar, T.; Su,
D.; Tang, H.; Wua, W.-L.; Zhang, L.; Zhao, Z. Bioorg. Med. Chem. Lett. 2010, 20,
2591–2596.
O
S
Ph
O
S
Ph
Ph
Ph
, 90%
MeO
4o
4p
, 92%
Scheme 3. Products of combination of PhCH2SH and PhCHO with substituted
acetophenones.

4408
M. S. Abaee et al. / Tetrahedron Letters 53 (2012) 4405–4408
5. Khatik, G. L.; Sharma, G.; Kumar, R.; Chakraborti, A. K. Tetrahedron 2007, 63,
1200–1210.
32. Gruttadauria, M.; Giacalone, F.; Marculesco, A. M.; Meo, P. L.; Riela, S.; Noto, R.
Eur. J. Org. Chem. 2007, 4688–4698.
6. Chen, C.-T.; Lin, Y.-D.; Liu, C.-Y. Tetrahedron 2009, 65, 10470–10476.
7. Lenardão, E. J.; Ferreira, P. C.; Jacob, R. G.; Perina, G.; Leite, F. P. L. Tetrahedron
Lett. 2007, 48, 6763–6766.
33. Breslow, R. Acc. Chem. Res. 2004, 37, 471–478.
34. Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem., Int. Ed.
Engl. 2007, 46, 3798–3800.
8. Bakuzis, P.; Bakuzis, M. L. F. J. Org. Chem. 1981, 46, 235–239.
9. Cherkauskas, J. P.; Cohen, T. J. Org. Chem. 1992, 57, 6–8.
10. Cohen, T.; Mura, A. J., Jr.; Shull, D. W.; Fogel, E. R.; Ruffner, R. J.; Falck, J. R. J. Org.
Chem. 1976, 41, 3218–3219.
11. Saito, M.; Nakajima, M.; Hashimoto, S. Tetrahedron 2000, 56, 9589–9594.
12. Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi,
A. J. Org. Chem. 2002, 67, 3700–3704.
13. Garg, S. K.; Kumar, R.; Chakraborti, A. K. Synlett 2005, 1370–1374.
14. Khan, A. T.; Ghosh, S.; Choudhury, L. H. Eur. J. Org. Chem. 2006, 2226–2231.
15. Banerjee, S.; Das, J.; Alvareza, R. P.; Santra, S. New J. Chem. 2010, 34, 302–306.
16. Yadav, J. S.; Reddy, B. V. S.; Baishya, G. J. Org. Chem. 2003, 68, 7098–7100.
17. Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2003, 59, 2417–2421.
18. Ranu, B. C.; Dey, S. S. Tetrahedron 2004, 60, 4183–4188.
19. Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195–206.
20. Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006.
21. Biggshouck, J. E.; Younai, A.; Shaw, J. T. Curr. Opin. Chem. Biol. 2010, 14, 371–
382.
22. Abaee, M. S.; Mojtahedi, M. M.; Pasha, G. F.; Akbarzadeh, E.; Shockravi, A.;
Mesbah, A. W.; Massa, W. Org. Lett. 2011, 13, 5282–5285.
23. Abaee, M. S.; Mojtahedi, M. M.; Navidipoor, S. Synth. Commun. 2011, 41, 170–
176.
24. Abaee, M. S.; Mojtahedi, M. M.; Forghani, S.; Ghandchi, N. M.; Forouzani, M.;
Sharifi, R. Chaharnazm. B J. Braz. Chem. Soc. 2009, 20, 1895–1900.
25. Mojtahedi, M. M.; Abaee, M. S.; Khakbaz, M.; Alishiri, T.; Samianifard, M.;
Mesbah, A. W.; Harms, K. Synthesis 2011, 3821–3826.
26. Abaee, M. S.; Mojtahedi, M. M.; Hamidi, V.; Mesbah, A. W.; Massa, W. Synthesis
2008, 2122–2126.
35. Lindstrom, U. M. Chem. Rev. 2002, 102, 2751–2772.
36. Zangi, R.; Hagen, M.; Berne, B. J. J. Am. Chem. Soc. 2007, 129, 4678–
4686.
37. Kalra, A.; Tugcu, N.; Cramer, S. M.; Garde, S. J. Phys. Chem. B 2001, 105, 6380–
6386.
38. Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289–296.
39. Abaee, M. S.; Mojtahedi, M. M.; Abbasi, H.; Fatemi, R. F. Synth. Commun. 2008,
38, 282–289.
40. Abaee, M. S.; Hamidi, V.; Mojtahedi, M. M. Ultrason. Sonochem. 2008, 15, 823–
827.
41. Typical procedure: A mixture of aldehyde (3 mmol), acetophenone (3 mmol),
and Et2NH (3 mmol) in 3 mL of degassed H2O was stirred at room temperature
for 3–5 hours until TLC showed complete disappearance of the reactants. The
thiol (3 mmol) was added to this mixture and stirring was continued for
another 4–6 min until TLC showed completion of the reaction. The product
precipitated and the mixture was filtered and the solid portion was
recrystallized from a mixture of petroleum ether and EtOAc to obtain the
pure product. The identity of known compounds 4a,b,d,g,i,j was confirmed by
comparison of their physical and spectroscopic data with those reported in the
literature. Compound 4c: Mp 75–77 °C; IR (KBr, cmÀ1) 1678, 1448, 1255; 1H
NMR (CDCl3) d 3.63 (dd, J = 6.0, 17.0 Hz, 1H), 3.68 (dd, J = 8.0, 17.0 Hz, 1H), 3.73
(s, 3H), 5.04 (dd, J = 6.0, 8.0 Hz, 1H), 6.79 (dd, J = 1.5, 8.2 Hz, 1H), 6.88 (dd,
J = 1.5, 1.5 Hz, 1H), 7.00 (dd, J = 1.5, 7.6 Hz, 1H), 7.19 (dd, J = 7.9, 8.0 Hz, 1H),
7.24–7.26 (m, 1H), 7.29–7.32 (m, 2H), 7.42 (d, J = 7.5 Hz, 2H), 7.46 (dd, J = 7.5,
8.0 Hz, 2H), 7.56–7.59 (m, 1H), 7.92 (d, J = 7.2 Hz, 2H) ppm; 13C NMR (CDCl3) d
45.2, 48.5, 55.6, 114.3, 117.8, 125.1, 127.8, 128.3, 128.5, 128.9, 129.1, 130.1,
133.7, 135.9, 137.2, 141.7, 160.1, 197.4 ppm; MS (70 eV): m/z 348 (M+), 207,
140, 105; Anal. Calcd for C22H20O2S: C, 75.83; H, 5.79. Found: C, 75.43; H, 5.64.
Compound 4e: Mp 68–70 °C; IR (KBr, cmÀ1) 1680, 1465, 1242; 1H NMR (CDCl3)
d 3.52–3.62 (m, 4H), 3.84 (s, 3H), 4.54 (dd, J = 6.9, 7.3 Hz, 1H), 6.87 (d, J = 8.5,
Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.29 (dd, J = 7.0, 7.5 Hz, 1H), 7.38 (dd, J = 7.5,
8.0 Hz, 2H), 7.45–7.48 (m, 4H), 7.58 (dd, J = 7.0, 7.5 Hz, 1H), 7.91 (d, J = 7.5 Hz,
2H) ppm; 13C NMR (CDCl3) d 35.8, 44.6, 45.8, 55.7, 114.3, 127.7, 128.5, 129.0,
129.1, 130.3, 130.5, 133.6, 137.2, 142.4, 159.1, 197.2 ppm; MS (70 eV): m/z 362
(M+), 207, 152, 121, 105; Anal. Calcd for C23H22O2S: C, 76.21; H, 6.12. Found: C,
76.49; H, 6.31.
27. Abaee, M. S.; Mojtahedi, M. M.; Zahedi, M. M.; Sharifi, R.; Khavasi, H. Synthesis
2007, 3339–3344.
28. Kumar, A. Akanksha Tetrahedron Lett. 2007, 48, 8730–8734.
29. Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354–10355.
30. Li, H.; Zu, L.; Xie, H.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9, 1833–
1835.
31. The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals; O’Neil, M.
J., Ed.; Merck & Co., Inc.: Whitehouse Station, 2001.