Solvent-free conjugated addition of thiols to citral using KF/alumina: preparation of 3-thioorganylcitronellals, potential antimicrobial agents

Article abstract of DOI:10.1016/j.tetlet.2007.07.103

A general, clean and easy method for the conjugated addition of thiols to citral promoted by KF/Al₂O₃ under solvent-free conditions at room temperature or under MW irradiation is described. It was found that the same protocol is appl

Full text of DOI:10.1016/j.tetlet.2007.07.103

Tetrahedron Letters 48 (2007) 6763–6766
Solvent-free conjugated addition of thiols to citral using
KF/alumina: preparation of 3-thioorganylcitronellals,
potential antimicrobial agents
a
a
a
Eder J. Lenardao,a, Patrıcia C. Ferreira, Raquel G. Jacob, Gelson Perin
*
´
˜
b
´
and Fabio P. L. Leite
a
ˆ
Instituto de Quı´mica e Geociencias, LASOL, Universidade Federal de Pelotas, UFPel, PO Box 354,
96010-900 Pelotas, RS, Brazil
bInstituto de Biologia, Universidade Federal de Pelotas, UFPel, PO Box 354, 96010-900 Pelotas, RS, Brazil
Received 4 June 2007; revised 3 July 2007; accepted 13 July 2007
Available online 25 July 2007
Abstract—A general, clean and easy method for the conjugated addition of thiols to citral promoted by KF/Al2O3 under solvent-
free conditions at room temperature or under MW irradiation is described. It was found that the same protocol is applicable to the
direct reaction of thiophenol with essential oil of lemon grass (Cymbopogon citratus) to afford directly 3-thiophenylcitronellal, a
potential bactericide agent. The method was extended to others electron-poor alkenes with excellent results. The catalytic system
can be reused up to three times without previous treatment with comparable activity.
Ó 2007 Elsevier Ltd. All rights reserved.
Besides important commodities in the flavor and fra-
grance industry, the natural occurring a,b-unsaturated
aldehyde citral, together with its analog citronellal,
are key compounds in organic synthesis.1 The conju-
gated addition (Michael addition) of thiols to a,b-unsat-
urated compounds (electron-poor alkenes) is a very
useful method for new carbon–sulfur bond-forming in
organic synthesis.2 This reaction also plays critical roles
in the biosynthesis and synthesis of bioactive com-
pounds.3 Besides, the 1,4-addition is a highly atom-effi-
cient, green reaction, in agreement with the principle #2
of the green chemistry.4 In view of these aspects, there is
a large number of reported methods for both basic and
acidic promoted selective 1,4-additions, including hetero-
geneous5 and homogeneous catalyses6 and asymmetric
versions.7 Thus, solid catalysts, such as basic anion-
exchange resins,5a natural5b and synthetic phosphates,5c
montimorillonite clays,5d solid potassium carbonate,5e
base5f and acid supported in alumina5g have been used
to perform the 1,4-addition of thiols to a series of elec-
tron-poor alkenes. However, the use of solid-supported
catalysts in Michael addition to a,b-unsaturated alde-
hydes was not explored.5
In the last years, our group has studied the use of renew-
able feed stocks in organic synthesis, following the green
and sustainable chemistry principles.1,8 As a continua-
tion of our studies, we describe here the solvent-free syn-
thesis of new 3-thioorganylcitronellal derivatives (3a–e),
starting from citral (1a) and thiols (2a–e) using KF/
Al2O3 as catalyst (Scheme 1, Table 1).9,10
Our initial efforts were made towards the determination
of the optimum conditions to perform the protocol.
Thus, we choose citral (1a), easily available from the
essential oil of lemon grass (Cymbopogon citratus) and
thiophenol (2a) to establish the best conditions for the
Michael addition.
RS
CHO
CHO
KF/Al2O3 (50%)
R
SH
+
r.t. or MW (548 W)
2
Keywords: Solvent-free; 1,4-Addition of thiols; Microwave irradiation;
Citronellal; Citral.
R = C6H5,
o
n
-ClC6H4,
p-CH3OC6H4
1a
3a-e
-C3H7, -C12H25
n
*
Corresponding author. Tel./fax: +55 53 3275 7354; e-mail:
lenardao@ufpel.edu.br
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.103

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E. J. Lenarda˜o et al. / Tetrahedron Letters 48 (2007) 6763–6766
Table 1. Conjugated addition of thiols to citral and electron-poor alkenes under solvent-free conditions
Entry
1
Alkene 1
Thiol 2
Product
Methoda
Time
4 h
Yieldb (%)
70
C6H5S
CHO
CHO
C6H5SH 2a
A
1a
3a
2
3
1a
1a
2a
3a
B
6 min
7.5 h
65
50
n-C3H7S
CHO
n-C3H7SH 2b
A
3b
4
5
1a
1a
2b
3b
B
1 min
7.5 h
67
60
n-C12H25
S
CHO
C12H25SH 2c
A
3c
6
7
1a
1a
2c
3c
B
2 min
9 h
35
70
o
-ClC6H4S
CHO
o-ClC6H4SH 2d
A
3d
8
9
1a
1a
2d
3d
B
0.5 min
8 h
38
81
p
-MeOC6H4S
CHO
p-MeOC6H4SH 2e
A
3e
10
11
1a
2e
3e
B
1 min
2 h
90
95
O
O
C6H5SH 2a
A
C6H5S
C6H5S
4
1b
1c
CN
CN
O
12
13
2a
2a
A
A
1 h
96
94
5
O
0.5 h
C6H5S
OCH3
OCH3
1d
6
O
O
14
2a
A
3 h
80
C6H5S
OH
OH
1e
7
a Method A: The experiments were performed at room temperature. Method B: The experiments were performed under MW at 548 W.
b Yields in pure products isolated by chromatography (AcOEt/hexanes) and identified by mass spectra, 1H and 13C NMR.

E. J. Lenarda˜o et al. / Tetrahedron Letters 48 (2007) 6763–6766
6765
With the aim to promote the selective 1,4-nucleophilic
addition, several reaction conditions were tested, and
the best results were obtained when KF/Al2O3 (50%,
0.07 g) was added to a mixture of citral (1a, 1 mmol)
and thiophenol (2a, 1.2 mmol) at room temperature
and stirred for 4 h (Table 1, entry 1).10
of renewable and easily available starting materials, no
solvent is necessary and the catalytic system can be re-
used. The use of microwaves accelerates the reaction
with comparable yields in most of the examples. Studies
looking for synthetic applications of these new sulfur-
containing citronellal derivatives are in course in our
laboratory and will be described soon.
The use of a larger amount of KF/Al2O3 (50%), or of a
larger concentration of KF (60% m/m) did not
increase the yield of 3a. On the other hand, using
0.050 g of KF/Al2O3 (50%) at room temperature makes
the reaction proceed slowly, in 40% yield after 12 h.
Aiming to reduce the reaction time, the mixture was
irradiated with microwaves. The product 3a was
obtained in good yield after 6 min of irradiation at
548 W (Table 1, entry 2). It was observed that the pro-
tocol works with aromatic and aliphatic thiols, and it
can be extended to a variety of electron-poor alkenes
(ester, acid, nitrile and ketone). The experimental proce-
dure is very easy, and the products were obtained after
stirring a few hours at room temperature or irradiated
for few minutes with microwaves (Table 1). The best
conditions were extended to others thiols 2 and a series
of 3-thioorganylcitronellals were obtained in moderate
to good yields (Table 1, entries 3–10). It was observed
that the catalytic system can be re-used for three cycles,
just by washing it with ethyl acetate and drying under
vacuum. The recycled catalytic system was successfully
employed to both the methods, at room temperature
and under microwave irradiation.
Acknowledgements
This project is funded by CNPq, FAPERGS and in part
by a grant from the ChemRAWN XIV International
Green Chemistry Grants Program. Professor C. C. Sil-
1
veira (UFSM/Brazil) is acknowledged for the H and
13
´
´
ˆ
C NMR analysis and Polo Oleoquımico de Tres Pas-
´
sos/UNIJUI for providing the essential oil of lemon
grass.
References and notes
1. Lenardao, E. J.; Botteselle, G. V.; Azambuja, F.; Perin,
˜
G.; Jacob, R. G. Tetrahedron 2007, 63, 6671.
2. Fluharty, A. L. In The Chemistry of Thiol Group; Patai, S.,
Ed.; Wiley: New York, 1974; p 589, Part 2.
3. (a) Hall, I. H.; Lee, K.-H.; Mar, E. C.; Starnes, C. O.;
Waddell, T. G. J. Med. Chem. 1977, 20, 333; (b) Paterson,
I.; Laffan, D. D. P.; Rawson, D. J. Tetrahedron Lett. 1988,
29, 1461.
4. (a) Anastas, P. T.; Warner, J. Green Chemistry: Theory
and Practice; Oxford University Press: Oxford, 1998; (b)
Lenardao, E. J.; Freitag, R. A.; Dabdoub, M. J.; Batista,
A. C.; Silveira, C. C. Quim. Nova 2003, 26, 123; (c) Trost,
B. M. Science 1991, 254, 1471.
5. (a) Li, M.; Huang, J.; Zahng, W. React. Funct. Polym.
2001, 47, 71; (b) Abrouki, Y.; Zahouly, M.; Rayadh, A.;
Bahlaouan, B.; Sebti, S. Tetrahedron Lett. 2002, 43, 8951;
(c) Zahouily, M.; Abrouki, Y.; Rayadh, A. Tetrahedron
Lett. 2002, 43, 7729; (d) Sharma, G.; Kumar, R.;
Chakraborti, A. K. J. Mol. Catal. A 2007, 263, 143; (e)
Keiko, N. A.; Funtikova, E. A.; Stepanova, L. G.;
Chuvashev, Y. A.; Larina, L. I. ARKIVOC 2001, 67; (f)
Moghaddam, F. M.; Bardajee, G. R.; Veranlou, R. O. C.
Synth. Commun. 2005, 35, 2427; (g) Bartoli, G.; Bartolacci,
M.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.; Tor-
regiani, E. J. Org. Chem. 2005, 70, 169.
6. See, for instance (a) Yadav, J. S.; Reddy, B. V. S.; Baishya,
G. J. Org. Chem. 2003, 68, 7098; (b) Ranu, B. C.; Dey, S.
S.; Hajra, A. Tetrahedron 2003, 59, 2417; (c) Manickam,
G.; Sundararajan, G. Tetrahedron 1999, 55, 2721.
7. For a review on enantioselective conjugated additions, see
Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
8. See, for example (a) Jacob, R. G.; Perin, G.; Loi, L. N.;
Due to our interest in the synthetic use of the essential
oils of plants cultivated in southern Brazil and their con-
stituents as raw material of renewable source for use in
organic synthesis,1,8 we tried to use one of our reaction
conditions (KF/Al2O3 (50%) under MW) in the direct
1,4-addition of thiophenol to the crude lemon grass oil
(C. citratus). The major component of the essential oil
of lemon grass, extracted from the plant that grew in
southern Brazil, was found to be citral (80–85%).11
Thus, when a mixture of thiophenol (2a) and the essen-
tial oil of lemon grass was submitted to MW irradiation
(548 W) for 0.5 min in the presence of KF/Al2O3 (50%,
0.07 g), 3-thiophenylcitronellal (3a) was obtained in 52%
yield, together with unreacted mircene, linalool, geraniol
and other minor constituents of the starting oil, which
were recovered.
The 3-thioorganylcitronellal derivatives 3a–e were tested
for their antimicrobial activity and preliminary studies
showed that all of them present bactericide activity
against Staphylococcus sp. The antimicrobial activity
of some 3-thioorganylcitronellals was higher than that
observed for the parent citral or even for non-function-
alized citronellal.
Pinno, C. S.; Lenardao, E. J. Tetrahedron Lett. 2003, 44,
˜
3605; (b) Jacob, R. G.; Perin, G.; Botteselle, G. V.;
Lenardao, E. J. Tetrahedron Lett. 2003, 44, 6809; (c)
Lenardao, E. J.; Mendes, S. R.; Ferreira, P. C.; Perin, G.;
˜
Silveira, C. C.; Jacob, R. G. Tetrahedron Lett. 2006, 47,
7439.
˜
In conclusion, we have presented here an easy and gen-
eral method for the preparation of new 3-thioorganyl-
citronellal derivatives with antimicrobial activity. This
eco-friendly protocol can be successfully applied to the
synthesis of 3-thiophenylcitronellal (3a) from crude
lemon grass oil, avoiding the necessity for separation
of citral (1a). The procedure is very simple, makes use
9. Preparation of alumina supported potassium fluoride:12 To
a 100 mL beaker were added alumina (4.0 g of Al2O3 90,
0.063–0.200 mm, Merck), KFÆ2H2O (6.0 g) and water
(10 mL). The suspension was stirred for 1 h at 65 °C,
dried at 80 °C for 1 h and for additional 4 h at 300 °C in
an oven and then cooled in a desiccator. The content of
KF is about 50% (m/m).

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E. J. Lenarda˜o et al. / Tetrahedron Letters 48 (2007) 6763–6766
10. General procedure for the 1,4-addition of thiols 2 to
electron-poor alkenes 1. Method A: To a mixture of citral
(1a, 0.152 g; 1 mmol) and thiophenol (2a, 0.13 g;
1.2 mmol), KF/Al2O3 (0.07 g, obtained as described
above) was added. The mixture was stirred at room
temperature. The reaction progress was followed by TLC,
and after 4 h the product was filtered off the aluminum
oxide by washing with ethyl acetate (10 mL). The solvent
was evaporated under reduced pressure and the residue
was purified by column chromatography over silica gel
(SiO2) eluting with hexane/ethyl acetate (97:3), yielding
product 3a (0.183 g, 70%) as a colorless oil. 1H NMR
(200 MHz, CDCl3) d (ppm) 9.95 (t, J = 2.6 Hz, 1H); 7.47–
753 (m, 2H); 7.34–7.43 (m, 3H); 5.03–5.10 (m, 1H); 2.46
(d, J = 2.6, 2H); 2.05–2.28 (m, 2H); 1.69 (s, 3H); 1.64 (s,
3H); 1.56–1.64 (m, 2H); 1.37 (s, 3H); 13C NMR (50 MHz,
CDCl3) d (ppm) 201.5, 137.4, 131.9, 130.5, 129.0, 128.6,
123.2, 52.1, 49.5, 40.2, 26.0, 25.5, 22.8, 17.5. MS m/z (rel.
int., %) 243 (M+ÀH2O, 1.9), 134 (73.8), 81 (90.8), 69
(100.0). Method B: The aforementioned whole mixture
was previously stirred for 1 min and then irradiated
with microwave (a domestic Panasonic model Piccolo
NN–S42BK operating at 2.45 MHz) at 548 W13 for 0.5–
6 min and the product was purified according to on
Method A.
11. Paviani, L.; Pergher, S. B. C.; Dariva, C. Braz. J. Chem.
Eng. 2006, 23, 219.
12. See, for example (a) Saikia, D.; Khanuja, S. P. S.; Kahol,
A. P.; Gupta, S. C.; Kumar, S. Curr. Sci. 2001, 80, 1264;
(b) Schuck, V. J. A.; Fratini, M.; Rauber, C. S.;
Henriques, A.; Schapoval, E. E. S. Braz. J. Pharm. Sci.
2001, 37, 45.
13. The oven powers were determined as described by
Kingston, H. M. In Introduction to Microwave Sample
Preparation—Theory and Practice; Jassie, L. B., Ed.;
American Chemical Society: DC, 1988.