Multicomponent, solvent-free synthesis of β-aryl-β-mercapto ketones using zirconium chloride as a catalyst

Article abstract of DOI:10.1016/j.tetlet.2007.10.023

Zirconium chloride efficiently catalyzes the one-pot, three-component reaction of an aryl aldehyde, cyclic or acyclic enolizable ketones, and thiols under solvent-free conditions at room temperature to afford the corresponding β-aryl-β-mercaptoketones via aldol-Michael addition reactions. This methodology affords a large number of β-aryl-β-mercapto ketone derivatives in high yields and in short reaction times.

Full text of DOI:10.1016/j.tetlet.2007.10.023

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Tetrahedron Letters 48 (2007) 8730–8734
Multicomponent, solvent-free synthesis of b-aryl-b-mercapto
ketones using zirconium chloride as a catalystI
Atul Kumar* and Akanksha
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, UP, India
Received 30 May 2007; revised 27 September 2007; accepted 3 October 2007
Available online 6 October 2007
Abstract—Zirconium chloride efficiently catalyzes the one-pot, three-component reaction of an aryl aldehyde, cyclic or acyclic enol-
izable ketones, and thiols under solvent-free conditions at room temperature to afford the corresponding b-aryl-b-mercaptoketones
via aldol-Michael addition reactions. This methodology affords a large number of b-aryl-b-mercapto ketone derivatives in high
yields and in short reaction times.
Ó 2007 Elsevier Ltd. All rights reserved.
9
Multi-component reactions are useful and efficient
methods in organic synthesis. The major advantages of
these reactions are (1) a single purification step, (2) high-
er yields than stepwise assembly, (3) the use of simple
and diverse precursors to construct complex molecules,
and (4) the use of only a single promoter or catalyst.
Thus, the development of new multi-component reac-
tions is a popular area of research in current organic
chemistry and is also acceptable from a ‘Green Chemis-
try’ point of view.1
InCl3,7 Cu(BF4)2ÆxH2O,8 Zn(ClO4)2 and NaOH,10
KOH,11 Ba(OH)2,12 hydrotalcites,13 and Cp2ZrH2/
NiCl2,14 for aldol condensation reactions. However,
both of these reactions require cumbersome workup
and purification steps. Most of these procedures have
several drawbacks, are time consuming and produce lots
of waste products.
Recently, zirconium chloride chemistry has attracted
much attention as ZrCl4 has emerged as an alternative
safe, economical, air, and moisture tolerant Lewis
acid which has been used in various organic
transformations.15
b-Aryl-b-mercapto ketones are valuable synthetic scaf-
folds for medicinal as well as synthetic organic chemists.
b-Aryl-b-mercapto ketones are useful for the synthesis
of various biologically active compounds such as, thio-
chromans,2 thiopyrans3 benzothiazapines,4 4,5-dihydro-
isoxazoles, 4,5-dihydropyrazoles.5 etc. Traditionally
the synthesis of b-aryl-b-mercapto ketones is performed
by a sequence of two separate reaction steps, (i) synthe-
sis of an a,b-unsaturated ketone via an aldol reaction,
(ii) 1,4-conjugate addition of a thiol to an a,b-unsatu-
rated ketone via a thia-Michael addition. Michael addi-
tion of a thiol to chalcone is an efficient approach to
prepare b-aryl-b-mercapto ketones. Consequently, there
are several reports in the literature for thia-Michael
addition utilizing natural and synthetic phosphates,6
Therefore, we investigated a zirconium chloride cata-
lyzed one-pot, simple, mild, and efficient procedure for
the rapid construction of b-aryl-b-mercapto ketones
via a three-component aldol-Michael addition reaction
between substituted cyclic or acyclic enolizable ketones
1, aryl aldehydes 2, and thiols 3 (Scheme 1).
To the best of our knowledge there is no report on the
one-pot synthesis of b-aryl-b-mercapto ketones in the
literature.
Initially, a model one-pot, three-component reaction of
acetophenone 1a (1.0 mmol), benzaldehyde 2a
(1.0 mmol) and thiophenol 3a (1.8 mmol) was planned
(Scheme 2). Several Lewis acids were screened in our
model reaction (Table 1).
Keywords: Zirconium chloride; One-pot; Multi-component reaction;
b-Aryl-b-mercapto ketones.
q CDRI Communication No. 7239.
*
Interestingly, the use of other Lewis acids such as AlCl3,
Corresponding author. Tel.: +91 522 261241 1; fax: +91 522
SnCl4, ZnCl2, and BF3ÆOEt2 slowed the reaction and
2623405; e-mail: dratulsax@gmail.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.023

A. Kumar, Akanksha / Tetrahedron Letters 48 (2007) 8730–8734
8731
SH
O
R2
R1
R3
8
3
Method-A
R2
O
H
O
R3
R3
SH
3
Method-B :
O
1
R2
S
R
Zirconium chloride catalyzed one- pot,
three - component reaction
1
2
or
5
4 or 6
R1
Scheme 1. Method-A (a) Clasein–Schmidt reaction or aldol type reaction, (b) thia-Michael addition reaction. Method-B (c) zirconium chloride
catalyzed one- pot, three-component reaction.
PhS
SPh
SH
COMe
CHO
COMe
CHO
SH
O
ZrCl4-SiO2
4a
Lewis acid
stir, r.t.
S
Solvent-free,
r.t.
4a
2a
3a
1a
7
3a
1a
2a
Scheme 3.
Scheme 2.
Various solvents such as EtOH, MeCN, CH2Cl2, THF,
Et2O, and PhMe were also screened for this reaction.
The best results were observed under solvent-free
conditions.
Table 1. One pot, three-component synthesis of 4a using different
Lewis acidsa
Entry
Lewis acid
Time (h)
Yieldb (%)
In order to investigate the catalyst loading in our model
reaction, the procedure was optimized using different
molar concentrations of zirconium chloride under
solvent-free conditions at room temperature (Table 2).
A high yield of adduct 4a was observed using
40 mol % of catalyst while with 20–30 mol % of catalyst,
a mixture of aldol 8 and Michael adduct 4a was
obtained. From these results, it was evident that the
catalyst concentration plays a crucial role in limiting
the reaction to yield products 4a or 8. This supported
the fact that the reaction proceeds via a one-pot aldol-
Michael condensation. An increased mol % of catalyst
did not improve the result to any greater extent.
1
2
3
4
5
6
7
8
9
No cat
ZnCl2
AlCl3
SnCl4
BF3ÆOEt2
TiCl4
ZrCl4
ZrCl4/SiO2
SiO2
24
8
6
10
12
4
1
1
2
—
NR
10
Trace
14
10
92
40/48c
45c
Reaction conditions:
a Benzaldehyde (1.0 mmol), acetophenone (1.0 mmol), thiol
(1.8 mmol), catalyst (30–40 mol %), rt.
b Isolated yield.
c Isolated yield of product 7.
Table 2. Effect of catalyst loading on the one-pot, three-component
resulted in a small or trace amount of the desired prod-
uct. It was found that only AlCl3 gave a minor amount
of b-aryl-b-mercapto ketone 4a along with other side
products. While ZrCl4 gave a high yield of 4a within a
short time, a high molar percentage of the catalyst was
required. Thus, in order to enhance the reactivity of
the catalyst, silica supported ZrCl4 (ZrCl4–SiO2) was
used. Surprisingly, and contrary to our expectations,
thioacetylated product 7 was obtained as the major
product along with 4a as a minor product (Scheme 3).
reactiona
b
Entry
ZrCl4 (%)
Time (h)
Ratioc
4a (Michael):8 (Aldol)
1
2
3
4
5
10
20
30
40
50
4.5
2.5
2.0
1.0
0.8
1.0:4.0
2.0:5.2
6.0:2.2
9.2:0.2
9.0:0.1
Reaction conditions:
a Benzaldehyde (1.0 mmol), acetophenone (1.0 mmol), thiol
(1.8 mmol), rt.
Therefore, ZrCl4 alone was found to be the most effec-
tive Lewis acid catalyst for the one-pot, three-compo-
nent synthesis of b-aryl-b-mercapto ketone 4.
b Zirconium chloride (mol %).
c Ratio of 4a (Michael):8 (aldol, PhCOCH@CHPh) product.

8732
A. Kumar, Akanksha / Tetrahedron Letters 48 (2007) 8730–8734
Table 3. Zirconium chloride catalyzed one-pot, three-component reaction of substituted benzaldehydes with substituted acetophenones and thiolsa–d
15
Entry
R1
R2
R3
Productc,
Time (h)
Yieldd (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
H
H
H
H
H
3-NO2
H
4-OMe
3-Cl
H
4a
4b
4c
4d
4e
4f
1.0
1.0
1.2
1.5
1.2
1.0
1.2
1.8
1.5
1.0
1.0
0.5
0.5
1.2
1.5
92
96
90
9517
94
92
90
88
85
92
90
92
9018
89
87
4-Me
4-Cl
H
4-Me
4-Cl
H
H
H
H
4-Me
H
4-OMeb
4-OMeb
4-OMeb
H
b
4g
4h
4i
4-OHb
H
4- Me
4- Me
4-OMeb
4-OMeb
H
4j
3-Cl
4k
4l
4-OMe
4-OMe
2, 6-C l
Ph
4-Me
H
H
4m
4n
4o
H
Reaction conditions:
a Aldehyde (1.0 mmol), ketone (1.0 mmol), thiol (1.8 mmol), ZrCl4 (40 mol %), solvent-free, rt.
b Dry CH2Cl2 (1–2 ml) used for solid reactants.
c Product characterized by IR, 1H, 13C NMR, and mass spectroscopy.
d Isolated yield (%) after crystallization.
In a further investigation, a sequential one-pot reaction
of benzaldehyde (1.0 mmol) and acetophenone
(1.0 mmol) in the presence of zirconium chloride
(20 mol %) was performed, leading to in situ generation
of chalcone 8. The progress of the reaction was moni-
tored by TLC. After the complete consumption of benz-
aldehyde and acetophenone, thiophenol (2 mmol) and
zirconium chloride (20 mol %) were added to the same
flask. Product 4a was obtained in 85–90% yield in
1–2 h. Encouraged by this initial result, a one-pot,
three-component reaction was performed by the simple
mixing of benzaldehyde (1.0 mmol), acetophenone
(1.0 mmol), thiophenol (1.8 mmol), and 40 mol % of
zirconium chloride. In comparison to the sequential
one-pot reaction, the three-component procedure gave
a comparatively high yield of 4a within 1 h without
any side product.16
To explore the generality and scope of this method, a
wide variety of substituted aromatic aldehydes and
acetophenones were reacted with substituted thiols
under the same experimental conditions to afford
the corresponding b-aryl-b-mercapto ketones. ZrCl4
was found to be compatible with various substituents
(electron withdrawing as well as donating substitu-
ents) such as OMe, OH, NO2, Cl, and Me and
the resultant products were obtained in good to
excellent yields in short reaction times (Table 3)
(Scheme 4).
To further extend the scope and utility of this procedure,
the reaction between an aromatic aldehyde 2, a cyclic
enolizable ketone (substituted tetralone, cyclohexanone)
5, and substituted thiophenols 3 was investigated
(Scheme 5).
R2
R3
O
O
R3
R2
O
R1
SH
H
R1
CH3
ZrCl
4 ( 40 mol% )
S
solvent free, r.t.
4a-o
1
2
3
Scheme 4.
R3
O
H
O
SH
O
S
ZrCl
4 ( 40 mol% )
R2
solvent-free, r.t.
R3
R2
5
6a-e
R2 = H
2
3
Scheme 5.

A. Kumar, Akanksha / Tetrahedron Letters 48 (2007) 8730–8734
8733
O
H
O
O
major
SH
6I-
ZrCl
4( 40 mol% )
solvent free, r.t.
O
S
2a
5d
3a
6d-
minor
Scheme 6.
Table 4. Zirconium chloride catalyzed one-pot, three-component coupling reaction of benzaldehyde with cyclic enolizable ketones and substituted
thiophenolsa,d
Entry
R3
Cyclic ketone
Productc
Time (h)
Yieldd
1
2
3
4
5
H
4-Me
H
H
4-Me
Tetralone
Tetralone
6-OMe tetraloneb
Cyclohexanone
6-OMe tetraloneb
6a
6b
6c
6d
6e
1.0
1.8
1.5
1.8
1.2
90
94
88
10
80
Reaction conditions:
a Aldehyde (1.0 mmol), ketone (1.0 mmol), thiol (1.8 mmol), ZrCl4 (40 mol %), solvent-free, rt.
b Dry CH2Cl2 (1–2 ml) used for solid reactants.
c Product characterized by IR, 1H, 13C NMR, and mass spectroscopy.
d Isolated yield (%) after crystallization.
Ulaczyk-Lesankom, A.; Hall, D. G. Curr. Opin. Chem.
Biol. 2005, 9, 266.
It was noticed that the reaction of cyclohexanone, benz-
aldehyde, and thiophenol with a catalytic amount of
zirconium chloride (40 mol %) furnished the unexpected
bis aldol product 6I as the major product along with a
minor amount of the desired product (6d) (Scheme 6).
2. (a) Kaye, P. T.; Nocanda, X. W. Synthesis 2001, 2389; (b)
Katritzky, A. R.; Button, M. A. C. J. Org. Chem. 2001, 66,
5595; (c) Kumar, P.; Bodas, M. S. Tetrahedron 2001, 57,
9755; (d) Ram, V. J.; Agarwal, N.; Saxena, A. S.;
Farhanullah, S.; Sharon, A.; Maulik, P. R. J. Chem.Soc.,
Perkin Trans. 1 2002, 1426.
3. (a) Al-Nakib, T.; Bezjak, V.; Rashid, S.; Fullam, B.;
Meegan, M. J. Eur. J. Med. Chem. 1991, 26, 221; (b)
Al-Nakib, T.; Bezjak, V.; Meegan, M. J.; Chandy, R. Eur.
J. Med. Chem. 1990, 25, 455; (c) Van Vliet, L. A.;
Rodenhuis, N.; Dijkstra, D.; Wikstroem, H.; Pugsley, T.
A.; Serpa, K. A.; Meltzer, L. T.; Heffner, T. G.; Wise, L.
D.; Lajiness, M. E.; Huff, R. M.; Svensson, K.; Sundell, S.;
Lundmark, M. J. Med. Chem. 2000, 43, 2871.
4. (a) Eudy, N. H.; Safir, S. R.; Press, J. B. J. Org. Chem.
1980, 45, 497; (b) Pant, S.; Sharma, A.; Sharma, C. K.;
Pant, U. C.; Goel, A. K. Indian J. Chem. 1996, 794; (c)
Desarro, G.; Chimirri, A.; Desarro, A.; Gitto, R.; Grasso,
S.; Zappala, M. Eur. J. Med. Chem. 1995, 30, 925; (d)
Braun, R. U.; Muller, T. J. J. Tetrahedron 2004, 60, 9463;
(e) Levai, A. J. Heterocycl. Chem. 2004, 41, 399.
5. Zielinska-Błajet, M.; Kowalczyk, R.; Skarzewski, J. Tetra-
hedron. 2005, 61, 5235.
6. (a) Zahouily, M.; Abrouki, Y.; Rayadh, A. Tetrahedron
Lett. 2002, 43, 7729; (b) Abrouki, Y.; Zahouily, M.;
Rayadh, A.; Bahlaouan, B.; Sebti, S. Tetrahedron Lett.
2002, 43, 8951.
Prolonging the reaction time and increasing the amount
of ZrCl4 catalyst to 80 mol % did not improve the yield
of the addition product 6d. On increasing the concentra-
tion of thiophenol, many other side products were
obtained. Good results were obtained with tetralones.
The results are summarized in Table 4.
All the products (Tables 3 and 4) obtained were fully
characterized by spectroscopic methods including IR,
1H NMR, 13C NMR, and mass spectroscopy and also
by the comparison of the spectral data with reported
values.17,18
In conclusion, this method provides an efficient multi-
component approach for the synthesis b-aryl-b-mer-
capto ketones. The reaction is versatile and also offers
several advantages, such as high yields, shorter reaction
times, cleaner reaction profiles and simple experimental
and work-up procedures.
7. Ranu, B. C.; Dey, S. S.; Samanta, S. ARKIVOC 2005, 44.
8. Garg, S. K.; Kumar, R.; Chakraborti, A. K. Tetrahedron
Lett. 2005, 46, 1721.
References and notes
1. (a) Dcmling, A.; Ugi, I. Angew. Chem. 2000, 112, 3300; (b)
Ramon, D. J.; Yus, M. Angew. Chem. 2005, 117, 1628; (c)
9. Garg, S. K.; Kumar, R.; Chakraborti, A. K. Synlett 2005,
1370.

8734
A. Kumar, Akanksha / Tetrahedron Letters 48 (2007) 8730–8734
10. Powers, D. G.; Casebier, D. S.; Fokas, D.; Ryan, W. J.;
Troth, J. R.; Coffen, D. L. Tetrahedron 1998, 54, 4085.
11. Bu, X.; Zhao, L. Y. Li Synthesis 1997, 1246.
12. Sinisterra, J. V.; Raso, A. G.; Cabello, J. A.; Marinas, J.
M. Synthesis 1984, 502.
13. Climent, M. J.; Corma, A.; Iborra, S.; Velty, A. J. Catal.
2004, 221, 474.
14. Nakamo, T.; Irifune, S.; Umano, S.; Inada, A.; Ishii, Y.
M. J. Org.Chem. 1987, 522, 239.
15. (a) Chakraborti, A. K.; Kondasker, A. Tetrahedron Lett.
2003, 44, 8315, and references cited therein; (b) Smitha,
G.; Reddy, S. C. Catal. Commun. 2007, 8, 434; (c) Kumar,
V.; Kaur, S.; Kumar, S. Tetrahedron Lett. 2006, 47, 7001.
16. General experimental procedure: Solvent-free: A mixture of
aromatic ketone 1 (1.0 mmol), aromatic aldehyde 2
(1.0 mmol), and zirconium chloride (40 mol %) and thiol
(1.8 mmol) was stirred vigorously at room temperature for
1.5–2 h. After the completion of the reaction, as indicated
by TLC, the reaction mixture was extracted with dichloro-
methane. The organic phase was dried (Na2SO4) and
filtered and concentrated under vacuum. The crude
product was obtained in 80–96% yield and purified by
simple crystallization to afford pure b-aryl-b-mercapto
ketone. All the products were characterized by 1H and
13C NMR spectroscopy.
17. Spectral data of selected compounds. 1-(4-Methoxy-phenyl)-
3-phenyl-3-phenylsulfanyl-propan-1-one, (4d); white solid,
1H NMR (200 MHz, CDCl3); d 3.52–3.59 (m, 2H), 3.83 (s,
3H), 4.91 (t, 1H, J = 6.2 Hz), 6.86 (d, 2H, J = 8.8 Hz),
7.16–7.34 (m, 10H), 7.83 (d, 2H, J = 8.8 Hz). 13C NMR
(50 MHz, CDCl3): d 44.7, 48.7, 55.8, 114.1, 127.7, 127.8,
128.2, 128.8, 129.2, 130.3, 130.7, 133.0, 134.7, 141.7, 164.0,
195.8. MS (FAB+) 348. Anal. Calcd for C22H20O2S: C,
75.83; H, 5.79. Found: C, 75.80; H, 5.77.
18. 1,3-Bis-(4-methoxy-phenyl)-3-p-tolyl-sulfanyl-propan-1-one.
1
(4m); white solid, H NMR (200 MHz, CDCl3): d 2.29 (s,
3H), 3.47–3.55 (m, 2H), 3.74 (s, 3H), 3.84 (s, 3H), 4.81 (t,
J = 6.1 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 6.86 (d,
J = 8.8 Hz, 2H), 7.05 (d, J = 7.9 Hz, 2H), 7.20–7.25 (m,
4H), 7.82 (d, J = 8.8 Hz, 2H,).13C NMR (50 MHz,
CDCl3): d 21.5, 44.7, 48.6, 55.6, 55.8, 114.1, 114.2, 129.2,
130.0, 130.3, 130.7, 131.0, 133.7, 138.0, 159.0, 163.9, 196.2.
MS (FAB+) 392. Anal. Calcd for C24H24O3S: C, 73.44; H,
6.16. Found: C, 73.46; H, 6.46.