Fast preparation of dihydrocyclocitral from citronellal under solventless microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2005.07.113

Dihydrocyclocitral, a useful reagent in organic synthesis, has been synthesized in high yield and with high stereoselectivity from citronellal under microwave irradiation in two steps, involving acetic anhydride under base catalysis, then p-toluenesulfonic acid adsorbed on silica gel under solventless conditions (80% yield, reaction time 22 min).

Full text of DOI:10.1016/j.tetlet.2005.07.113

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6749–6751
Fast preparation of dihydrocyclocitral from citronellal
under solventless microwave irradiation
Nhuan Ngoc Doan,a, Thach Ngoc Le,b Poul Erik Hansena and Fritz Duusa,*
aDepartment of Life Sciences and Chemistry, Roskilde University, PO Box 260, DK-4000 Roskilde, Denmark
bDepartment of Organic Chemistry, University of Natural Sciences, National University of Hochiminh City,
227 Nguyen Van Cu St., Dist. 5, Hochiminh City, Vietnam
Received 1 June 2005; revised 13 July 2005; accepted 22 July 2005
Available online 15 August 2005
Abstract—Dihydrocyclocitral, a useful reagent in organic synthesis, has been synthesized in high yield and with high stereoselectivity
from citronellal under microwave irradiation in two steps, involving acetic anhydride under base catalysis, then p-toluenesulfonic
acid adsorbed on silica gel under solventless conditions (80% yield, reaction time 22 min).
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
perature, for example, the preparation of the enol ester
required 7 h at 140 °C, and the subsequent cyclisation
reaction required reflux for about 1.5–3.0 h with strong
acids such as H3PO4 and H2SO4. The authors also
used reagents like TiCl4, CF3COOH, CH3SO3H,
BF3O(C2H5)2, but obtained lower yields.1,2
Dihydrocyclocitral, 2,2,6-trimethylcyclohexanecarbox-
aldehyde 1, is a useful starting material, for example,
for the preparation of many products of interest in the
flavour and pharmaceutical industries.1–4
Several synthetic pathways to dihydrocyclocitral from
different starting materials have been described. Corey
and Marcus synthesized 1 from 2,2,6-trimethylcyclo-
hexanone by reaction with 1-diphenylphosphonio-1-
methoxymethyllithium.5 Marcel prepared 1, also
starting from 2,2,6-trimethylcyclohexanone, via 1-eth-
oxymethyl-2,2,6-trimethylcyclohexanol.6 Simmons used
3,7-dimethyloct-7-enal, hydroxycitronellal as well as cit-
ronellal as starting materials to prepare 1 by two steps
via an intermediate enol ester and using various acids
to promote the ring-closure reaction. After purification
by vacuum distillation, the product was obtained in
about 60–65% yield (trans/cis isomers = 87/13).1
Yamamoto used this procedure to prepare 1 with high
purity in 51% yield from methoxycitronellal, the ratio
of trans/cis isomers being 90/10.2 However, all these
preparations required long reaction times at high tem-
Microwave heating can be very useful for otherwise rel-
atively slow reactions. Since the first publications on the
application of microwave-assisted organic synthesis in
the mid-1980s,7 this technology has been developing
rapidly.8 Organic synthesis under solventless conditions
is encouraged for environmental protection reasons.9
In this letter, we present a dihydrocyclocitral synthesis
following a Simmons-like procedure from citronellal 2,
however using a microwave (MW) oven instead of con-
ventional heating. The cyclisation reaction was carried
out under mild conditions by using p-toluenesulfonic
acid (PTSA) adsorbed on silica as catalyst in dry media.
The sequence is shown in Scheme 1.
2. Results and discussion
Enol ester 3 was prepared from citronellal 2 by reaction
with acetic anhydride in the presence of base under
microwave irradiation (see Scheme 1). We investigated
the significance of the molar ratio between 2 and
Ac2O, the reaction time and the base in order to opti-
mize the reaction conditions (Table 1).
Keywords: Dihydrocyclocitral; Citronellal; Microwave irradiation;
Solventless synthesis; Solid support; Isomeric selectivity.
*
Corresponding author. Tel.: +45 46742434; fax: +45 46743011;
e-mail: fd@ruc.dk
On leave from the University of Natural Sciences, National Univer-
sity of Hochiminh City, Vietnam.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.113

6750
N. N. Doan et al. / Tetrahedron Letters 46 (2005) 6749–6751
In order to investigate the cyclisation reaction, we puri-
fied 3 by vacuum distillation. The enol ester 3 was ob-
tained as a mixture of the (E) and (Z) isomers with a
purity of 97% (GC, E/Z = 64:36). The two geometrically
OAc
Ac2O
MW
CHO
CH(OAc)2
+
1
isomeric enol esters were identified by their H NMR
signals at d = 7.06 ppm (dd, J = 12.3, 0.6 Hz; @CH–
OCOCH3, (E)-form) and d = 6.99 ppm (dd, J = 6.6,
1.2 Hz; @CH–OCOCH3, (Z)-form).
2
3
4
PTSA
MW
The next step was the preparation of dihydrocyclocitral
by treatment of 3 with an acid.§ With strong acids such
as phosphoric or sulfuric acid, the reaction was very dif-
ficult to control under microwave conditions. Therefore,
we used PTSA as catalyst for cyclisation both with and
without silica gel (Table 2).
O
H
1
As shown in Table 2, dihydrocyclocitral was prepared in
an excellent yield (97%) with high isomeric selectivity
(trans/cis isomers = 97:3) within a few minutes under
solventless microwave irradiation using p-toluenesul-
fonic acid adsorbed on silica gel as catalyst. The trans
Scheme 1. Synthesis of dihydrocyclocitral from citronellal.
1
and cis isomers of dihydrocyclocitral showed in the H
Table 1. Preparation of enol ester 3 from citronellal 2 using MW
NMR spectrum the expected two high frequency reso-
nances at d = 9.65 ppm (d, J = 5.1 Hz, –CHO, trans
form) and d = 9.89 ppm (d, J = 6.6 Hz, –CHO, cis
form).5 The results proved that this catalyst promoted
the reaction under mild conditions. In the absence of sil-
ica, the reaction occurred, but did not give a good yield
owing to the formation of unexpected by-products (p-
cymene and dimeric materials).
irradiation
Entry 2:Ac2O
(molar ratio)
Time (min) Base
Yield of 3 (%)
1
2
3
4
5
6
7
8
1:4
20
20
K2CO3 87
K2CO3 87
1:3
1:2
1:3
1:3
1:4
1:3
1:3
1:3
1:3
1:3
20
25
15
15
420
420
25
20
15
K2CO3 72
K2CO3 86
K2CO3 74
K2CO3 80
K2CO3 86a
Et3N
Et3N
Et3N
Et3N
We also prepared 1 without purification (distillation) of
3, which gave dihydrocyclocitral in 80% total yield with
a purity of 98%.–
86a
85
86
70
9
10
11
Our investigation demonstrates that dihydrocyclocitral
1 can be synthesized from citronellal, following a
Simmons-like procedure,1 in an enhanced yield with an
enhanced isomeric selectivity and within a short time
by carrying out the two-step synthesis under solventless
conditions assisted by microwave irradiation.
a The reactions were refluxed by heating with stirring.
The results in Table 1 show that the yield of 3 was high-
est (87%) when the reaction was carried out under
microwave irradiation for 20 min with a molar ratio of
1:3 between citronellal and acetic anhydride.à Potassium
carbonate and triethylamine were equally suitable as
bases.
Spectral data of the enol ester 3, (E)-isomer (CDCl3): 1H
NMR (300 MHz) d 7.06 (dd, J = 12.3, 0.6 Hz; 1H), 5.29
(dd, J = 12.3, 8.7, 1H), 5.04–5.14 (m, 1H), 2.09–2.19 (m,
1H), 2.10 (s, 3H), 1.90–2.00 (m, 2H), 1.68 (d, J = 0.9,
§ Dihydrocyclocitral catalysed by p-toluenesulfonic acid on silica: p-
Toluenesulfonic acid (monohydrate, 99%, Aldrich, amounts see Table
2) was dissolved in water followed by the addition of silica (silica gel
60, Merck) in the ratio 1/6 (w/w). From this slurry, water was
removed completely by evaporation under reduced pressure at 60 °C
to give the desired catalyst. A mixture of the distilled enol ester 3
(97%, 6.0 g) and catalyst was treated in the microwave oven, MDS-
2000, CEM in a short time (see Table 2). The mixture was extracted
with diethyl ether, washed with water and dried (Na2SO4). After
removal of the solvent, the crude product was obtained according to
Table 2.
– Direct preparation of dihydrocyclocitral from citronellal: Citronellal
(26.4 g, 0.17 mol) was treated with acetic anhydride as described
above to give the crude enol ester 3. This material was used directly
for the preparation of 1. Vacuum distillation of the crude 1 (74–
75 °C/6 mbar), gave 20.2 g (total yield: 80%) of dihydrocyclocitral
with a purity of 98% (according to GC).
à 3,7-Dimethylocta-1,6-dien-1-yl acetate 3: A mixture of citronellal
(4.9 g, 30 mmol), acetic anhydride (see Table 1 for amounts),
potassium carbonate (4.1 g, 30 mmol) or triethylamine (5.6 g + 0.2 g
sodium acetate) was placed in the reaction vessel. The reactions were
carried out in a professional microwave oven, Maxidigest MX350,
Prolabo with reflux condenser. The temperature of the mixture was
142 °C. After adding diethyl ether (30 mL), the cooled reaction
mixture was washed (with water, aqueous NaHCO3 and brine) and
dried (Na2SO4). The solvent was removed by evaporation at reduced
pressure, and the residue was distilled at low pressure (67–75 °C/
1 mbar) to give 97% of 3 with an E/Z isomeric ratio of 64/36. The
pure isomers were obtained by a further fractional distillation
followed by column chromatography separation (eluent: n-hexane/
ethyl acetate = 95:5). A minor amount of diester 4 (5–8%) accompa-
nied 3 in the mixture and was isolated by continued fractional
distillation (98–100 °C/1 mbar).1

N. N. Doan et al. / Tetrahedron Letters 46 (2005) 6749–6751
6751
Spectral data of the diester 4 (CDCl3): 1H NMR
(300 MHz) d 6.87 (dd, J = 6.6, 4.8 Hz; 1H), 5.05–5.10
(m, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 1.93–2.03 (m, 2H),
1.74–1.83 (m, 1H), 1.68 (s, 3H), 1.60 (s, 3H), 1.52–1.59
(m, 2H), 1.19–1.41 (m, 2H), 0.96 (d, J = 6.0, 3H). 13C
NMR (75 MHz) 17.7, 19.6, 20.8, 20.9, 25.2, 25.7, 28.1,
37.0, 40.1, 89.7, 124.4, 131.5, 168.9, 169.0.
Table 2. MW induced cyclisation of enol ester 3 into dihydrocycloc-
itral 1
Entry 3:PTSA
(molar ratio)
Supports Time (min) Yield of 1 (%)
1
2
3
4
5
6
7
8
10:3
SiO2
SiO2
SiO2
SiO2
SiO2
Al2O3
0
0
0
0
0
1.5
1.5
1.0
2.0
1.5
2.0
1.5
2.0
3.0
2.0
1.5
97
94
91
93
48
—
50
62
74
82
72
10:2
10:2
10:2
10:1
10:2
10:2
10:2
10:2
10:3
10:3
a
Acknowledgements
We wish to thank DANIDA for their financial support
via the ENRECA programme.
9
10
11
a Basic Al2O3.
References and notes
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3H), 1.59 (s, 3H), 1.23–1.41 (m, 2H), 1.02 (d, J = 6.9,
3H). 13C NMR (75 MHz) 17.7, 20.7, 20.9, 25.7, 25.8,
32.0, 37.2, 120.6, 124.3, 131.5, 134.6, 168.2; (Z)-isomer:
1H NMR (300 MHz) d 6.99 (dd, J = 6.6, 1.2, 1H), 5.04–
5.14 (m, 1H), 4.67 (dd, J = 9.6, 6.6, 1H), 2.61–2.75 (m,
1H), 2.13 (s, 3H), 1.90–2.00 (m, 2H), 1.68 (d, J = 0.9,
3H), 1.59 (s, 3H), 1.20–1.43 (m, 2H), 0.99 (d, J = 6.9,
3H). 13C NMR (75 MHz) 17.6, 20.7, 22.7, 25.9, 29.3,
31.6, 37.4, 120.2, 124.5, 131.3, 133.2, 168.1.
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York, 2002.
Spectral data of dihydrocyclocitral 1 (CDCl3): 1H NMR
(300 MHz) d 9.89 (d, J = 6.6 Hz, –CHO, cis), 9.65 (d,
J = 5.1 Hz, –CHO, trans), several resonances were ob-
served in the range from 0.8 to 2.0 ppm. 13C NMR
(75 MHz) 20.8, 21.0, 21.7, 27.8, 31.0, 33.8, 34.3, 41.5,
66.2, 207.3. MS (m/e): 154 (M+, 28), 139 (14), 121
(31), 111 (39), 95 (28), 83 (64), 69 (100), 55 (57), 41 (50).
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Weinheim, 2003.