Green synthesis of (-)-isopulegol from (+)-citronellal: Application to essential oil of citronella

Article abstract of DOI:10.1016/S0040-4039(03)00714-7

A simple green and efficient method has been developed for the synthesis of (-)-isopulegol from (+)-citronellal in the presence of a solid supported catalyst (SiO₂/ZnCl₂), under solvent-free conditions and MW irradiation. It was also found that the same technology is applicable to the direct preparation of (-)-isopulegol from the essential oil of citronella (Cymbopogon nardus, growing in southern Brazil) in excellent yield.

Full text of DOI:10.1016/S0040-4039(03)00714-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3605–3608
Green synthesis of (−)-isopulegol from (+)-citronellal: application
to essential oil of citronella
Raquel G. Jacob,a,* Gelson Perin,a Leticia N. Loi,a Claudia S. Pinnoa and Eder J. Lenarda˜ob
a
´
Departamento de Biologia e Qu´ımica, Laborato´rio de Pesquisa em Qu´ımica-UNIJUI-98700-000 Iju´ı, RS, Brazil
bDepartamento de Qu´ımica Anal´ıtica e Inorgaˆnica, Universidade Federal de Pelotas-UFPel, Pelotas, RS, Brazil
Received 26 February 2003; revised 14 March 2003; accepted 17 March 2003
Abstract—A simple green and efficient method has been developed for the synthesis of (−)-isopulegol from (+)-citronellal in the
presence of a solid supported catalyst (SiO2/ZnCl2), under solvent-free conditions and MW irradiation. It was also found that the
same technology is applicable to the direct preparation of (−)-isopulegol from the essential oil of citronella (Cymbopogon nardus,
growing in southern Brazil) in excellent yield. © 2003 Elsevier Science Ltd. All rights reserved.
The ene-cyclisation of the monoterpene (+)-citronellal
(1) affording (−)-isopulegol (2) is the best industrial
process for the preparation of (−)-menthol (3),1,2 a fine
chemical widely employed in pharmaceuticals, agro-
chemicals, cosmetics, toothpastes, chewing gum and
other toilet goods. This methodology has also been
extended to the preparation of several natural com-
pounds with biological activities.3–5
In fact, among the methods for the conversion of 1 into
2, Lewis acids have shown the best catalytic activity,
especially concerning the selectivity aspects, since (−)-
isopulegol (2) was predominantly obtained among the
three other possible isomers 4–67–13 (Scheme 1). Aiming
to improve the reaction’s stereoselectivity to (−)-isop-
ulegol (2), several heterogeneous catalysts have been
studied and excellent results have been achieved by
using silica- and clay-supported catalysts.8–14
The (+)-citronellal, employed in the industrial process
for (−)-menthol preparation (Takasago process), is
obtained from myrcene through a three steps sequence,
being the isomerisation of geranyl diethylamine to (R)-
citronellal enamine, using a chiral Rh(I)–BINAP cata-
lyst as the key step. This reaction is performed at 100°C
in THF for 12 h, furnishing this enamine in 98% yield
and 98.5% ee.
Despite the heterogeneous catalytic system advantages
of performing the cyclisation of (+)-citronellal (1), the
methods described involve the use of hazardous sol-
vents, heating, high molar ratio of the catalyst/sub-
strate, expensive catalyst or the necessity for special
treatment for its activation and are also not time
efficient. These aspects are in disagreement with clean
chemistry, especially with respect to the green chemistry
In the Takasago process aqueous ZnBr2 is used to
perform the ene-cyclisation in very good yield and
excellent selectivity.1 More recently, the Takasago Co.
have patented the use of tris(2,6-diarylphen-
oxy)aluminum as a better catalyst for this cyclisation.6
Keywords: microwave; solvent-free reaction; isopulegol.
* Corresponding author. E-mail: rgjacob@unijui.tche.br
Scheme 1. a: SiO2/ZnCl2 (10%), MW (488 W).
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00714-7

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R. G. Jacob et al. / Tetrahedron Letters 44 (2003) 3605–3608
principles c5 and c6, that refer to the elimination of
the hazardous solvents and energy efficiency.15
cyclisation of 1 in excellent yield (Scheme 1, Table 1).
As a control experiment, the same reaction mixture was
heated at 58°C using an oil bath. The reaction progress
was followed by TLC and GC; after heating for 1 h, all
the citronellal was consumed. However, the cyclisation
products were obtained in only 72% yield, together with
byproducts and with loss of selectivity in comparison
with the experiment with MW (Table 1, entry 10). This
fact shows a clear advantage of microwave irradiation
over conventional heating techniques.
During recent years a large number of papers have been
advocating the advantages of ‘MORE Chemistry’
(microwave oven-induced reaction enhancement) as an
effective green technique in organic synthesis.16,17 When
used with an energy-efficient heating method, several
reactions under MW showed a dramatic increase in
yield, rate and purity of products. Of particular interest
are the MW dry reaction techniques or solvent-free
procedures using supported reagents.17 This technology
provides enhanced reaction rates, safety, ease of manip-
ulation and greater selectivity.
In order to evaluate the synergy between the solvent-
free medium and microwave irradiation in this reaction,
several experiments were carried out, as shown in Table
1. Silica gel and acidic alumina were used as inorganic
support to several Lewis acids (HCl, ZnCl2 and FeSO4).
When (+)-citronellal (1) was submitted to acidic cyclisa-
tion under MW in the absence of solid support or only
using SiO2 or acidic Al2O3, no reaction took place in all
conditions tested and 1 was recovered unchanged. By
using SiO2/HCl catalyst, (+)-citronellal reacted
smoothly to afford 2 as the predominant isomer, but
with poor selectivity (entry 1, Table 1). When ZnCl2
(10%) was supported on silica gel a higher selectivity
was achieved at reduced MW power and lower reaction
time (entry 4).
The clay-catalysed ring closure of (+)-citronellal (1) to
(−)-isopulegol (2) under MW was studied, but no effect
of the MW heating was observed.18 A solvent-free
variant protocol, involving the irradiation of
1
adsorbed on Na-Y-zeolites, showed good results.19 (−)-
Isopulegol (2) was obtained in 89% yield, together with
(+)-neoiso-isopulegol (6) (6%) and some dehydration
products of 2 and 6 (5%). However, this methodology
requires high molar ratio solid catalyst: 1 (8:1, wt/wt)
and its preparation demands a long time and the use of
organic solvents.
As a part of our efforts in exploring the utility of
citronellal in organic synthesis, we report here the
optimal conditions for the synthesis of (−)-isopulegol
(2) on solid supported Lewis acid under microwave
irradiation. It was found that SiO2/ZnCl2 (10%)20 under
MW (1.5 min; 488 W, 58°C)21 promotes the selective
Irradiation time and ratio of reactants were investigated
in order to make this microwave technology applicable
on a commercial scale (entries 2–11). As shown in
Table 1, increasing reaction time and ratio of the
reactants lead to higher yields and selectivity. Although
Table 1. Solvent-free solid supported cyclisation of (+)-citronellal (1) to (−)-isopulegol (2) under MW
Entry
Solid supported catalyst Solid catalyst: citronellal; mmol
Reaction time
(min)
Conversionb
(%)
Isomeric ratioc (%)
(ratio wt/wt)
2
4
5
6
1
2
3
4
5
6
7
8
SiO2/HCl
2:1 (1:1.3)
2:1 (1:1.2)
2:1 (1:1.2)
2:1 (1:1.2)
10:5 (1:1.2)
4:1 (1.6:1)
4:1 (1.6:1)
20:5 (1.6:1)
40:10 (1.6:1)
80:20 (1.6:1)
400:100 (1.6:1)
2:1 (1:1.3)
2:1 (1:1.3)
4:1 (1.6:1)
4:1 (1.3:1)
2:1 (1.3:1)
4:1 (2.7:1)
30a
7
8
100
98
98
98
90
90
98
98
100
100
100
98
80
80
70
80
80
51
33
44
59
56
55
60
68
77
76
74
48
60
57
40
63
40
22
11
20
24
26
23
35
28
23
24
26
38
36
43
30
25
26
27
56
34
12
18
20
–
–
d
SiO2/ZnCl2 (10%)
SiO2/ZnCl2 (10%)
SiO2/ZnCl2 (10%)
SiO2/ZnCl2 (10%)
SiO2/ZnCl2 (10%)
SiO2/ZnCl2 (10%)
SiO2/ZnCl2 (10%)
SiO2/ZnCl2 (10%)
SiO2/ZnCl2 (10%)
SiO2/ZnCl2 (10%)
SiO2/FeSO4 (4%)
SiO2/FeSO4 (4%)
SiO2/FeSO4 (4%)
Al2O3/HCl
2
10
10
5
10
10
10
1.5
1.5
4
10
5
15
15
15
5
d
2
5
4
–
–
–
–
4
–
2
6
2
–
d
9
d
d
10
11
12
13
14
15
16
17
14
–
–
28
6
32
Al2O3/ZnCl2 (7%)
Al2O3/FeSO4 (1.2%)
a The power of the MW oven was calibrated at 662 W; all the others experiments were performed at 488 W.24
b Determined by GC.
c Determined by GC and 1H NMR of the crude reaction mixture and compared after purification.
d Traces of this isomer was detected by GC.

R. G. Jacob et al. / Tetrahedron Letters 44 (2003) 3605–3608
3607
most experiments were performed on a 1.0 mmol scale,
References
we have also explored scaling-up these reactions (10–
100 mmol) and comparable yields were achieved
(entries 7–11). Interestingly, when the reactions were
performed with 20 and 100 mmol of 1 and a solid
supported catalyst: 1 ratio=1.6:1 (wt/wt), (−)-isopule-
gol (2) was obtained in excellent yield with 76–74%
selectivity, together with (+)-neo-isopulegol (7) and
traces the isomer 5, after irradiation for 1.5 min (entries
10 and 11, Table 1).
1. Misono, M.; Nojiri, N. Appl. Catal. 1990, 64, 1.
2. Akutagawa, S. In Chirality in Industry; Collins, A. N.;
Sheldrack, G. N.; Crosby, J., Eds.; John Wiley, 1992; pp.
313–323.
3. Kim, J. H.; Lim, H. J.; Cheon, S. H. Tetrahedron Lett.
2002, 43, 4721.
4. Yuasa, Y.; Tsuruta, H.; Yuasa, Y. Org. Proc. Res. Dev.
2000, 4, 159.
5. Ferreira, J. T. B.; Zarbin, P. H. G. Bioorg. Med. Chem.
1996, 4, 381.
6. Takeshi, I.; Yoshiki, O.; Yoji, H. European Patent
When SiO2/FeSO4 (4%) was used in place of SiO2/
ZnCl2 (10%), both yield and stereoselectivity of the
cyclisation reaction were lowered (entries 12–14). Simi-
larly, the use of the acidic alumina as support was
studied. However, MW irradiation for 5–15 min failed
to provide satisfactory yields and selectivity of (−)-isop-
ulegol (entries 15–17). Attempts to directly reuse the
solid supported catalysts in a new cyclisation reaction
were unsuccessful, there was a loss of catalytic activity.
However, the solid supports were regenerated by new
treatment with ZnCl2.20 The SiO2/ZnCl2 (10%) pre-
pared with used SiO2 showed the same catalytic activ-
ity, affording 2 in almost identical yield.
EP1225163, July 24, 2002.
7. Nakatani, Y.; Kawashima, K. Synthesis 1978, 147.
8. Arata, K.; Matsuura, C. Chem. Lett. 1989, 1797.
9. Kropp, P. J.; Breton, G. W.; Craig, S. L.; Crawford, S.
D.; Durland, W. F., Jr.; Jones, J. F., III; Raleigh, J. S. J.
Org. Chem. 1995, 60, 4146.
10. Ravasio, N.; Antenori, M.; Babudri, F.; Gargano, M.
Stud. Surf. Sci. Catal. 1997, 108, 625.
11. Aggarwal, V. K.; Vennall, G. P.; Davey, P. N.; Newman,
C. Tetrahedron Lett. 1998, 39, 1997.
12. Milone, C.; Gangemi, C.; Neri, G.; Pistone, A.; Gal-
vagno, S. Appl. Catal. A: Gen. 2000, 199, 239.
13. Milone, C.; Perri, A.; Pistone, A.; Neri, G.; Galvagno, S.
Appl. Catal. A: Gen. 2002, 233, 151.
14. For a review in the use of clay and clay-supported
reagents in organic synthesis, see: Varma, R. S. Tetra-
hedron 2002, 58, 1235.
To extend the scope of the reaction, our best catalytic
system (SiO2/ZnCl2, 10%) was submitted to the essen-
tial oil of citronella (Cymbopogon nardus (L) Rendle).
The major component of the essential oil of citronella,
extracted from the plant grown in southern Brazil (Treˆs
Passos, RS), was found to be (+)-R-citronellal (40–
51%).22 Thus, selective cyclisation of citronellal to isop-
ulegol was observed in excellent yield (100% of
conversion) and comparable stereoselectivity,23 when
the essential oil of citronella was submitted to MW
irradiation for 1 min under 427 W24 in the presence of
SiO2/ZnCl2 (10%). (−)-Isopulegol (2) was obtained in
75% yield, together with 4 (15%) and 5 (10%). Unre-
acted geraniol, citronellol, geranyl acetate, and other
minor constituents of the starting oil were recovered.
15. Anastas, P. T.; Warner, J. Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, 1998.
16. For a review concerning the use of MW and other
non-classical energy fonts in organic synthesis, see:
Nu¨chter, M.; Ondruschka, B.; Jungnickel, A.; Mu¨ller, U.
J. Phys. Org. Chem. 2000, 13, 579.
17. For reviews in MW solvent-free using supported
reagents, see: (a) Varma, R. S. Green Chem. 1999, 43; (b)
Varma, S. Pure Appl. Chem. 2001, 73, 193.
18. Laurent, R.; Laporterie, A.; Dubac, J.; Berlan, J.; Lefeu-
vre, S.; Audhuy, M. J. Org. Chem. 1992, 57, 7099.
19. Ipaktschi, J.; Bru¨ck, M. Chem. Ber. 1990, 123, 1591.
20. The solid supported catalysts were prepared by the fol-
lowing procedures: SiO2/HCl catalyst: To a 250 mL
beaker was added silica gel (10.0g of silica gel 60, 230–
240 mesh, Merck) and 5% HCl (100 mL). The suspension
was stirred at room temperature for 30 min and the
resulting mixture was filtered under reduced pressure,
dried at 150°C for 15 h in an oven and then cooled in a
desiccator. The same procedure was used for Al2O3/HCl
(10.0g of Al2O3 90, 0.063–0.200 mm, Merck). SiO2/ZnCl2
(10%): To a 100 mL beaker was added silica gel 60 (9.0g),
ZnCl2 (1.0g) and water (3.0 mL). The suspension was
stirred for 15 min at room temperature, dried at 80°C for
3 h and for an additional 15 h at 150°C in an oven and
then cooled in a desiccator. The aforementioned proce-
dure was used for SiO2/FeSO4 (4%; 9.6:0.4 g), Al2O3/
ZnCl2 (7%; 9.3:0.7 g) and Al2O3/FeSO4 (1.2%; 9.88:0.12
g) by varying the Lewis acid and its amount.
In conclusion, (−)-isopulegol was prepared directly
from the treatment of essential oil of citronella under
solid supported acid catalysis and solvent-free MW
assisted ene-cyclisation. This environmentally benign
method involves a low consumption of solvent, simple
work-up, short reaction time, mild reaction conditions,
excellent yields and high selectivity. The elimination of
hazardous and expensive solvents and auxiliaries,
together with the low energy consumption, make this
method potentially useful for the green production of
(−)-isopulegol on a commercial scale, starting from
citronella oil.
Acknowledgements
The authors thank SCT-RS, FAPERGS and CNPq for
financial support, Professor A. L. Braga from the Fed-
eral University of Santa Maria for helpful discussions
and the NMR and IR analysis, and Po´lo Oleoqu´ımico
de Treˆs Passos, RS, for the essential oil of citronella.
21. (−)-Isopulegol (2) from (+)-citronellal (1): To a 250 mL
reaction flask equipped with a septum port and contain-
ing SiO2/ZnCl2 (10%) (2.54 g; 40 mmol), (+)-citronellal 1
(1.54 g; 10 mmol) was added dropwise. The reaction

3608
R. G. Jacob et al. / Tetrahedron Letters 44 (2003) 3605–3608
mixture was irradiated in an unmodified household
22. Gherke, I. T. S.; Bourscheid, L. R.; Gobo, A. B.
Resumos da 25a Reunia˜o Anual da Sociedade Brasileira
de Qu´ımica, Poc¸os de Caldas, Brazil, 2002.
MW oven (Brastemp model VIP-38 Sensor Crisp oper-
ating at 2.45 GHz) at 488 W.24 The reaction progress
was followed by GC. After 1.5 min, the reaction vessel
was cooled, and the product was extracted from the
silica gel with ethyl acetate (20 mL) and filtered. The
solvent was evaporated under reduced pressure to
afford a mixture of 2 and 4 (1.54 g; 100% yield, ratio
2:4=76:24), together with traces of 5, as a colorless oil.
The isomers were identified by 1H NMR, in particular
from the proton CHO signals, and the isomers ratio
were determined by GC analysis. The spectral data of 2
and 4 were in perfect agreement with those reported in
the literature.7,9 IR (film, cm−1): 3389, br (OH). 1H
NMR (200 MHz, CDCl3) l (2): 4.87 (m, 1H); 4.83 (s
br, 1H); 3.43 (dt, J=10.4 and 4.3 Hz, 1H); 2.03 (m,
1H); 1.86 (m, 1H); 1.69 (d, J=0.5 Hz, 3H); 1.65 (m,
2H); 1.49 (m, 2H); 1.32 (m, 1H); 0.97 (m, 2H); 0.92 (d,
J=6.5 Hz, 3H). (4): 3.67 (dt, J=10.4 and 4.2 Hz, 1H).
23. (−)-Isopulegol (2) from essential oil of citronella: To a
250 mL reaction flask equipped with a septum port and
containing SiO2/ZnCl2 (10%) (2.54 g; 40 mmol), essen-
tial oil of citronella (1.54 g; 40% of citronellal, deter-
mined by GC analysis) was added dropwise. The
reaction mixture was irradiated at 427 W for 1.0 min,
the reaction vessel was cooled at room temperature and
the product was extracted from the silica gel with ethyl
acetate (20 mL) and filtered. The solvent was evapo-
rated under reduced pressure yielding a mixture of 2, 4
and 5 (ratio 2:4:5=75:15:10) and other unreacted oil
constituents.
24. The oven powers were determined according to:
Kingston, H. M. In Introduction to Microwave Sample
Preparation, Theory and Practice; Jassie, L. B., Ed.;
American Chemical Society: Washington DC, 1988.