Regioselective catalytic acetoxylation of limonene

Article abstract of DOI:10.1039/c4cy00231h

Two efficient strategies for a direct catalytic and regioselective acetoxylation of terpenes are described. Acetoxylated limonene derivatives were synthesized via palladium-catalyzed C-H activation utilizing para-benzoquinone (BQ) as reoxdidation agent and acetic acid as solvent and reactant. Addition of dimethyl sulfoxide (DMSO) to the catalytic system led to highly selective functionalization of the exocyclic double bond of limonene. This catalytic acetoxylation of limonene was further optimized with regard to a more sustainable and environmentally-friendly procedure. On the other hand, the use of an aerobic tandem catalytic system using iron(ii) phthalocyanine (Fe(Pc)) as co-catalyst, which acts as electron transfer mediator (ETM), enabled a highly selective acetoxylation of the endocyclic double bond of limonene with high conversions. Moreover, diacetoxylated products were prepared by a reaction sequence applying the aforementioned catalytic systems.

Full text of DOI:10.1039/c4cy00231h

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Regioselective catalytic acetoxylation of limonene
Marc von Czapiewski and Michael A. R. Meier*
Cite this: Catal. Sci. Technol., 2014,
4, 2318
Two efficient strategies for a direct catalytic and regioselective acetoxylation of terpenes are described.
Acetoxylated limonene derivatives were synthesized via palladium-catalyzed C–H activation utilizing
para-benzoquinone (BQ) as reoxdidation agent and acetic acid as solvent and reactant. Addition of
dimethyl sulfoxide (DMSO) to the catalytic system led to highly selective functionalization of the exocyclic
double bond of limonene. This catalytic acetoxylation of limonene was further optimized with regard to
a more sustainable and environmentally-friendly procedure. On the other hand, the use of an aerobic
tandem catalytic system using iron(II) phthalocyanine (Fe(Pc)) as co-catalyst, which acts as electron transfer
mediator (ETM), enabled a highly selective acetoxylation of the endocyclic double bond of limonene with
high conversions. Moreover, diacetoxylated products were prepared by a reaction sequence applying the
aforementioned catalytic systems.
Received 20th February 2014,
Accepted 29th April 2014
DOI: 10.1039/c4cy00231h
www.rsc.org/catalysis
of oxygenated limonene derivates using a selenium dioxide/
hydrogen peroxide system. The resulting products bear hydroxy-
Introduction
The development of sustainable processes using renewable
feedstocks is an important and urgent challenge, not only
due to the depletion of fossil resources. With an increasing
and epoxy functional groups, which are obtained by oxida-
tion at the corresponding allylic position or double bond.
11
1
Da Silva et al. reported an oxyfunctionalization protocol for
the autoxidation of limonene using acetic acid or acetonitrile
as solvent and a cobalt(II) chloride catalyst. Within this cata-
lytic procedure, the respective internal epoxidized limonene,
carvone and carveolis were obtained in moderate yields after
demand of fossil-derived raw materials the price of crude oil
will increase dramatically, thus promoting the search for suit-
2
able alternatives. Renewable raw materials (e.g. starch, fats
and oils, cellulose, and others), represent a valuable alterna-
tive to fossil resources. Already today, nine million tons of
renewable raw material derived products are used within the
European industry per year, demonstrating their remarkable
1
2
four hours at 60 °C. Another interesting approach for the
oxyfunctionalization of limonene is realized by a tandem cata-
lytic system using palladium(II) chloride/copper(II) chloride in
the presence of lithium chloride and acetic acid. Gusevskaya
and Gonsalves described an efficient catalytic process that
enabled the preparation of trans-carveyl acetate with high con-
version of 87% after four hours at 80 °C. However, small
amounts of different oxidized and isomerized products were
3
potential. Among the available renewable materials, terpenes
constitute a valuable and cheap biomass resource, which
are available in large scales from various essential oils or
4
–6
as by-product from diverse industrial processes.
Terpenes
are secondary metabolites synthesized by plants, fungi and
microorganisms. Furthermore, terpenes are of great interest
for humans, due to their versatile application possibilities,
e.g. as flavors, fragrances, nutrients, pheromones or as phar-
13
formed as well. Firdoussi et al. reported the synthesis of
regioselectively acetoxylated limonene derivates under mild
reaction conditions and long reaction times of 48 hours. By
using a tandem catalytic system consisting of palladium(II)
chloride/copper(II) chloride and sodium acetate in acetic acid
as solvent, high conversion of 90% were obtained. However,
due to allylic acetoxylation at the endocyclic double bond,
three different products were formed. The same group also
described a catalytic system making use of palladium(II) ace-
tate as catalyst and stoichiometric amounts of p-benzoquinone
7
–9
macological substrates. The remarkable structural diversity
of terpenes, containing cycloaliphatic, aromatic or diene moi-
1
0
eties offers versatile functionalization possibilities. Thus, in
order to synthesize diverse value added terpene compounds,
the development of efficient and catalytic derivatization pro-
cesses are of great interest. Especially, a selective oxidation
of terpenes is highly desirable from an economic and ecologic
point of view, since these terpene derivatives are used in a wide
range of applications. Wilson and Shaw reported the synthesis
14
as reoxidation agent. Under mild reaction conditions of 20 °C,
two internally acetoxylated products were formed in good con-
version of 80%. Unfortunately, long reaction times (72 h) were
15
required to obtain the corresponding products. White and
colleagues reported the synthesis of acetoxylated α-olefins by a
highly selective allylic C–H oxidation process. The remarkable
Laboratory of Applied Chemistry, Institute of Organic Chemistry, Karlsruhe
Institute of Technology (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany.
E-mail: m.a.r.meier@kit.edu; Web: www.meier-michael.com
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selectivity of this catalytic procedure is accomplished by a
sulfoxide-promoted oxidation using palladium(II) acetate as
catalyst and p-benzoquinone. Depending on the employed
sulfoxide agent, linear or branched acetoxylated products were
obtained. The aforementioned catalytic systems usually require
stoichiometric amounts of an oxidizing agent (e.g. p-benzoquinone)
to facilitate the regeneration of palladium(II) species and to
avoid the precipitation of the catalyst. Interestingly, Piera
and Bäckvall recently published an oxidation protocol for the
aerobic 1,4-diacetoxylation of 1,3 dienes by a tandem catalytic
system that involved an electron transfer mediator (ETM),
which allowed for an efficient oxidation reaction. One major
advantage of such an aerobic tandem procedure is the use of
catalytic amounts of the oxidizing agent, e.g. p-benzoquinone,
which is regenerated during the catalytic process by an iron(II)
p-benzoquinone (1.47 mmol, 1.0 eq.), 0.25 g molecular
sieves (3 Å), and 29.0 mg n-tetradecane (0.15 mmol, 10.0 mol%)
as internal standard were added and the mixture was stirred
for five minutes at 50 °C. Then, 13.2 mg palladium(II) acetate
(0.06 mmol, 4.0 mol%) was added and the mixture was stirred
for 24 hours at 50 °C. The crude reaction mixture was washed
with water, sodium hydrogen carbonate and brine, dried over
sodium sulfate and evaporated to dryness. Afterwards, the crude
product was purified by column chromatography (hexane/ethyl
acetate 95: 5) to afford an orange-yellow liquid. The product
was obtained as a mixture of the major product 2 and small
amounts of the by-products (enantiomers 3 and 4 as well as
5 and 6).
16,17
General procedure for the synthesis of acetoxylated products
via aerobic tandem catalytic system
phthalocyanine co-catalyst (ETM).
Thus, it would be highly
interesting to make use of such an oxidation protocol to
achieve an efficient and selective functionalization of terpene
substrates. Therefore, in order to allow an efficient and regio-
selective functionalization of limonene, we report two oxida-
tion methods: the palladium-catalyzed C–H activation process
using dimethyl sulfoxide and an aerobic tandem catalytic sys-
tem using an ETM. Moreover, the two catalytic procedures
were used in a sequential reaction procedure to synthesize
diacetoxylated limonene derivatives. The thus prepared limonene
derivatives are valuable precursors for step-growth polymeri-
zations. Additionally, these limonene derivatives are valuable
precursors for organic synthesis, i.e. for transition metal cata-
lyzed allylic substitution reactions.
0.20 g (S)-(−)-limonene 1 (1.47 mmol), 41.7 mg iron(II) phtha-
locyanine (0.07 mmol, 5.0 mol%), 32.3 mg hydroquinone
(0.29 mmol, 20 mol%), 60.2 mg sodium acetate (0.74 mmol,
0.5 eq.), and 29.0 mg n-tetradecane (0.15 mmol, 10.0 mol%)
as internal standard were dissolved in 3.0 mL acetic acid
and stirred for five minutes at 60 °C. Subsequently, 16.5 mg
palladium(II) acetate (0.07 mmol, 5.0 mol%) was added and
the mixture was stirred for 24 hours at 60 °C. The crude reac-
tion mixture was washed with water, sodium hydrogen car-
bonate, and brine, dried over sodium sulfate and evaporated
to dryness. Afterwards, the crude product was purified by
column chromatography (hexane/ethyl acetate 95 : 5) to afford
a slightly yellow liquid. The product was obtained as a mix-
ture of the major products of enantiomers 3 and 4 as well
as 5 and 6 and a small amount of by-product 2.
Experimental section
Materials
(
S)-(−)-Limonene (96%, Sigma Aldrich), palladium(II) acetate (98%,
General procedure for the synthesis of diacetoxylatedproducts
Sigma Aldrich), iron(II) phthalocyanine (dye content ~ 90%, Sigma
Aldrich), hydroquinone (99%, Sigma Aldrich), p-benzoquinone
0
.20 g 2 (1.03 mmol, 1.0 eq.), 29.3 mg iron(II) phtha-
locyanine (0.05 mmol, 5.0 mol%), 22.7 mg hydroquinone
0.21 mmol, 20 mol%), 42.2 mg sodium acetate (0.52 mmol,
.5 eq.) were dissolved in 3.0 mL acetic acid and stirred for
(>98%, Sigma Aldrich), acetic acid (>96%, Roth), dimethyl
(
0
sulfoxide (DMSO, >99, 5%, Roth), sodium acetate (anhydrous,
Sigma Aldrich), sodium sulfate (>99% anhydrous, Acros Organics),
tetrahydrothiophene (99%, Sigma Aldrich), α,α,α-trifluorotoluene
five minutes at 60 °C. Subsequently, 11.6 mg palladium(II)
acetate (0.05 mmol, 5.0 mol%) was added and the mixture
was stirred for 5 days at 60 °C. The crude reaction mixture
was washed with water, sodium hydrogen carbonate, and
brine, dried over sodium sulfate and evaporated to dryness.
Afterwards, the crude product was purified by column chro-
matography (hexane/ethyl acetate 95 : 5) to afford a yellow
liquid in 37% yield (95.0 mg). The obtained product was
isolated as a mixture of enantiomers 7 and 8 as well as 9
and 10.
(
>99%, Sigma Aldrich),sodium hydrogen carbonate (>95%,
Sigma Aldrich), tetradecane (>99%, Sigma Aldrich), silica gel
0 (0.040–0.063, Sigma Aldrich), TLC silica gel F254 (Merck),
chloroform-d (CDCl , 99.8 atom % D, Euroiso-top), potassium
permanganate (>99%, Sigma Aldrich), potassium carbonate
99.7%, Sigma Aldrich), sodium hydroxide (98%, Sigma Aldrich),
6
3
(
molecular sieve (3Å, Sigma Aldrich), acetonitrile, dimethyl-
formamide, dimethylacetamine, n-hexane, ethyl acetate. All
solvents were used without further purification.
(S)-2-(4-Methylcyclohex-3-en-1-yl)allyl acetate 2. Orange-yellow
liquid, yield (148 mg, 52%); R
f
: = 0.35 (hexane/ethyl acetate 95 : 5);
1
H-NMR: (600 MHz, CDCl ) δ/ppm 5.41–5.28 (m, 1H, CH),
3
General procedure for the synthesis of acetoxylated products
via palladium-catalyzed process using DMSO and acetic acid
5
2
.05 (s, b, 1H, CH ), 4.97 (s, b, 1H, CH ), 4.58 (s, b, 2H, CH ),
2
2
2
.28–2.12 (m, 1H, CH), 2.13–1.98 (m, 2H, CH
2
), 2.12–1.88
0
1
.20 g (S)-(−)-limonene 1 (1.47 mmol) were dissolved in
(m, 2H, CH ), 2.09 (s, 3H, CH ), 1.96–1.82 (m, 1H, CH ),
2 3 2
1.65 (s, 3H, CH ), 1.53–1.46 (m, 1H, CH ).
3 2
.5 mL DMSO and 1.5 mL acetic acid. Additionally, 0.16 g
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1
3
CNMR: (75 MHz, CDCl ) δ/ppm 170.9, 148.4,.133.9, 120.4,
(s, 1H, CH ), 4.56 (s, 2H, CH ), 2.43–2.30 (m, 1H, CH),
3
2
2
1
11.1, 66.3, 37.2, 31.2, 30.5, 28.0, 23.5, 21.1.
2.29–2.19 (m, 2H, CH ), 2.07 (s, 3H, CH ), 2.06 (s, 3H, CH ),
2
3
3
+
SEC/ESI-MS of [C12
17.08.
H
18
O
2
Na ]: calculated: 217.12, found:
2.04–1.95 (m, 1H, CH
3H, CH ).
2
), 1.69–1.64 (m, 1H, CH
2
), 1.68 (s, b,
2
3
1
3
IR (ATR platinum diamond): 2916.1, 1736.6, 1646.3, 1436.7,
370.8, 1220.5, 1149.6, 1097.1, 1022.8, 967.2, 912.3, 797.4,
59.1, 604.0, 523.1, 429.8 (Fig. 1).
CNMR: (75 MHz, CDCl ) δ/ppm 170.9, 170.7, 147.2, 131.2,
3
1
7
127.5, 112.0, 70.4, 66.2, 33.9, 32.2, 31.2, 21.4, 21.0, 20.6.
ESI-MS: calculated: 252.14; found: 252.13.
Mixture of enantiomers (1R, 5S)-2-methyl-5-(pro-1-en-2-yl-)
cyclohex-2-en-1-yl acetate 3 and (1S, 5R)-2-methyl-5-(pro-1-
en-2-yl-)cyclohex-2-en-1-yl acetate 4. Light yellow liquid, yield
IR (ATR platinum diamond): 2935.2, 1730.2, 1649.5, 1438.0,
1368.7, 1224.6, 1155.0, 1097.4, 1025.0, 953.7, 911.3, 836.5, 807.9,
605.0, 549.4, 469.9, 437.8 (Fig. 1).
(
154 mg, 64%); R : = 0.40 (hexane/ethyl acetate 95 : 5);
Mixture of enantiomers 2-((1S, 3R)-3-acetoxy-4-methyl-
enecyclohexyl)allyl acetate 9 and 2-((1R, 3S)-3-acetoxy-4-
f
1
H-NMR: (600 MHz, CDCl
3
) δ/ppm 5.75–5.72 (m, 1H, CH),
5
.26 (t, J = 3.1 Hz, 1H, CH), 4.97 (t, J = 1.7 Hz, 1H, CH2),
methylenecyclohexyl)allyl acetate 10. Yellow liquid, yield
4
.87 (t, J = 1.8 Hz, 1H, CH ), 2.35–2.29 (m, 1H, CH), 2.24–2.20
(95.0 mg, 37%); R : = 0.21 (hexane/ethyl acetate 95 : 5);
2
f
1
(m, 1H, CH
2
), 2.08 (s, 3H, CH
3
), 1.97–1.93 (m, 1H, CH
2
),
3
H-NMR: (300 MHz, CDCl ) δ/ppm 5.39 (t, J = 3.0 Hz, 1H,
1
.90–1.84 (m, 1H, CH ), 1.73 (s, 3H, CH ), 1.70–1.68 (m, 3H, CH ),
CH), 5.06 (s, 1H, CH ), 4.96 (s, 1H, CH ), 4.96 (s, 1H,
2 2
2
3
3
1
.67–1.64 (m, 1H, CH ).
CH ), 4.86 (s, b, 1H, CH ), 4.54 (s, 2H, CH ), 2.54–2.43
2
2
2
2
1
3
CNMR: (75 MHz, CDCl
3
) δ/ppm 171.0, 148.9, 131.0, 128.0,
(m, 2H, CH
2
3 3
), 2.08 (s, 3H, CH ), 2.04 (s, 3H, CH ), 1.94–1.82
1
2
12.6, 70.8, 35.9, 33.8, 31.0, 21.5, 20.9, 20.8.
(m, 2H, CH ), 1.78–1.69 (m, 1H, CH), 1.62–1.51 (m, 1H, CH ),
2
2
+
SEC/ESI-MS of [C12
17.08.
H
18
O
2
Na ]: calculated: 217.12, found:
2
1.40–1.24 (m, 1H, CH ).
1
3
CNMR:(75 MHz, CDCl
3
) δ/ppm 170.8, 170.2, 147.3, 144.8,
IR (ATR platinum diamond): 2935.4, 1733.2, 1643.7, 1437.8,
368.0, 1232.2, 1149.9, 1073.6, 1045.4, 1016.1, 965.5, 950.6, 911.1,
87.8, 807.6, 673.6, 609.2, 538.0, 469.4, 437.0 (Fig. 1).
Mixture of enantiomers (1R, 5S)-2-methylene-5-(prop-1-
en-2-yl)cyclohexyl acetate 5 and (1S, 5R)-2-methylene-5-(prop-
112.9, 111.8, 74.1, 66.1, 37.3, 35.4, 32.6, 30.8, 21.5, 20.8.
ESI-MS: calculated: 252.14; found: 252.13.
IR (ATR platinum diamond): 2935.2, 1730.2, 1649.5, 1438.0,
1368.7, 1224.6, 1155.0, 1097.4, 1025.0, 953.7, 911.3, 836.5, 807.9,
605.0, 549.4, 469.9, 437.8 (Fig. 1).
1
8
1
-en-2-yl)cyclohexyl acetate 6. Light yellow liquid, yield (154 mg,
Characterization. Thin layer chromatography (TLC) was
performed on silica gel TLC-cards. Permanganate reagent was
used as staining reagent.
5
4%); R : = 0.40 (hexane/ethyl acetate 95 : 5);
f
1
H-NMR: (600 MHz, CDCl
3
) δ/ppm 5.41 (t, J = 3.1 Hz, 1H,
), 4.73–4.71 (m, 1H, CH ),
CH) 4.76–4.74 (m, 1H, CH
4
2
2
Optimization. Screening reactions were performed in a carousel
reaction station™ RR98072 (Radleys Discovery Technologies, UK).
.71–4.69 (m, 2H, CH ), 2.45–2.39 (m, 1H, CH), 2.39–2.35
2
1
13
(m, 1H, CH
2
), 2.29–2.26 (m, 1H, CH
2
), 2.06 (s, 3H, CH
3
),
NMR-analysis. H and C NMR spectra were recorded on
2
.05–2.00 (m, 1H, CH
2
), 1.90–1.84 (m, 1H, CH
2
), 1.71 (s, 3H,
Bruker Advance DPX spectrometers (Billerica, MA) with a 5 mm
1
13
CH ), 1.57–1.51 (m, 1H, CH ), 1.35–1.26 (m, 1H, CH ).
dual proton/carbon probe (300, 400 MHz H/75.5 MHz C)
and on a Bruker Advance III with a 5 mm z-gradient cryo-
3
2
2
1
3
3
CNMR: (75 MHz, CDCl ) δ/ppm 170.3, 149.0, 145.2, 109.3,
1
1
09.3, 74.4, 39.1, 37.0, 32.5, 30.9, 21.3, 21.0.
genically cooled probe head (CPTCI, 600 MHz H/75.5 MHz).
+
1
ESI-MS of [C H O Na ]: calculated: 217.12, found: 217.08.
H-NMR spectra were reported in ppm relative to TMS or to
1
2
18 2
1
3
IR (ATR platinum diamond): 2935.4, 1733.2, 1643.7, 1437.8,
368.0, 1232.2, 1149.9, 1073.6, 1045.4, 1016.1, 965.5, 950.6, 911.1,
87.8, 807.6, 673.6, 609.2, 538.0, 469.4, 437.0 (Fig. 1).
3
the solvent signal of CDCl at 7.26 ppm, and C-NMR spec-
1
8
tra were reported in ppm relative to the central signal of the
1
triplet for CDCl at 77.00 ppm. Data for H-NMR were reported
3
Mixture of enantiomers 2-((1S, 5R)-5-acetoxy-4-methylcyclohex-
-en-1-yl)allyl acetate 7 and 2-((1R, 5S)-5-acetoxy-4-methylcyclohex-
-en-1-yl)allyl acetate 8. Yellow liquid, yield (95.0 mg, 37%);
as follows: multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, b = broad), coupling constant (Hz),
integration, and assignment. Heteronuclear multiple quantum
coherence (HMQC), heteronuclear single quantum coherence
(HSQC) and heteronuclear multiple bond correlation (HMBC)
methods were used in order to characterize the structures.
3
3
f
R : = 0.21 (hexane/ethyl acetate 95 : 5);
1
3
H-NMR: (300 MHz, CDCl ) /δ/ppm 5.75–5.68 (m, 1H,
CH), 5.27–5.21 (m, 1H, CH), 5.08 (s, 1H, CH ), 4.96
2
Fig. 1 Palladium-catalyzed acetoxylation of (S)-(−)-limonene.
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−
1
GC-MS-analysis. GC-MS analysis was performed using a
Varian 431-GC instrument with a capillary column FactorFour™
VF-5 ms (30 m × 0.25 mm × 0.25 mμm) and a Varian 210-MS
detector. Scans were performed from 40 to 650 m/z at rate of
with a concentration of ~3 mg mL was injected onto the
HPLC system.
−1
1.0 scans min . The oven temperature program applied during
Results and discussion
the analysis was: initial temperature 95 °C, hold for 1 min,
−1
ramp at 15 °C min to 200 °C, hold for 2 min, ramp at
The aim of this investigation was the catalytic functionalization
of terpenes in order to synthesize regioselectively acetoxylated
compounds that also have the potential to be used for the synthesis
of renewable platform chemicals, especially for step-growth poly-
merization procedures. In this context, (S)-(−)-limonene (1), which
can be obtained from renewable feedstock, was explored towards
its reactivity in two different catalytic oxidations procedures.
−1
1
5 °C min to 300 °C, hold for 5 min. The injector transfer line
temperature was set to 250 °C. Measurements were performed
in the split–split mode (split ratio 50: 1) using helium as carrier
−1
gas (flow rate 1.0 ml min ).
Mass. Electron spray ionization mass spectra (ESI-MS) were
recorded on a Micromass Q-TOF instrument.
IR. Infrared spectra (IR) were recorded on a Bruker Alpha-p
−
1
instrument in a frequency range from 3997.21 to 373.942 cm
applying KBr- and ATR-technology.
Acetoxylation at the exocyclic double bond of (S)-(−)-limonene
SEC/ESI-MS. Spectra were recorded on a LXQ mass
spectrometer (Thermo Fisher Scientific, San Jose, CA) equipped
with an atmospheric pressure ionization source operating
in the nebulizer-assisted electrospray mode. The instrument
was calibrated in the m/z range 195–1822 using a standard
containing caffeine, Met-Arg-Phe-Ala acetate (MRFA), and a mixture
of flourinated phosphazenes (Ultramark 1621) (all from Aldrich).
A constant spray voltage of 4.5 kV, a dimensionless sweep gas
flow rate of 2, and a dimensionless sheath gas flow rate of
At first, a palladium-catalyzed C–H activation process using
DMSO in the presence of p-benzoquinone (BQ) as reoxidation
agent in acetic acid as solvent was investigated. The reaction
was optimized with regard to an acetoxylation of the exocyclic
double bond of limonene (Fig. 1).
The first catalytic system, which was introduced by White
and co-workers and highly promotes the allylic oxidation of
1
8
α-olefins, was transferred to (S)-(−)-limonene. The procedure
uses palladium(II) acetate/BQ and a solvent mixture of DMSO
and acetic acid. One major advantage of this catalytic oxida-
tion system is the formation of linear (E)-allylic acetates, which
can be obtained in good yields and with high regio- and stereo-
selectivity. A similar procedure has been successfully applied
to unsaturated fatty acid methyl esters (FAMEs) in order to
1
2 were applied. The capillary voltage, the tube lens offset
voltage, and the capillary temperature was set to 60 V, 110 V,
and 275 °C, respectively. The LXQ was coupled to a Series
1
200 HPLC-system (Agilnet, Santa Clara, CA) consisting of
a solvent degasser (G1322A), a binary pump (G1321A), and
a high-performance autosampler (G1367B), followed by a
thermostated column compartment (G1316A). Separation was
performed on two mixed bed sized exclusion chromatography
columns (Polymer Laboratories, Mesopore 2504.6 mm, parti-
cle diameter 3 μm) with precolumn (Mesopore 50–4.6 mm)
1
9
obtain the corresponding linear allylic acetates. Transferring
the procedure of White et al., who used 10 mol% of palladium
catalyst, to (S)-(−)-limonene resulted mainly in an acetoxylation
of the exocyclic double bond, which afforded the correspond-
ing functionalized product 2. As by-products, enantiomers 3
and 4 as well as enantiomers 5 and 6 were formed due to an
acetoxylation of the endocyclic double bond (Fig. 1). In this
process, a new stereocenter is created by two possible attacks
of the acetate (a′, a′′, Fig. 2), respectively. Since NMR cannot
distinguish between 3 and 4 as well as 5 and 6, it is fair to
assume and in accordance with the acetoxylation mechanism
that the enantiomer pairs (3/4 or 5/6, respectively) are formed
in a 1 : 1 ratio. The attack of the nucleophile only occurred as
depicted in Fig. 2, explaining why only one of the two possible
−
1
operating at 30 °C. THF at a flow rate of 0.30 mL min
was used as eluent. The mass spectrometer was coupled to the
column in parallel to an RI-detector (G1362A with SS420x A/D)
−
1
in a set-up described previously, 0.27 mL × min of the eluent
−
1
was directed through the RI detector, and 30 μL × min
was infused into the electrospray source after post column
addition of a 100 μM solution of sodium iodide in metha-
−
1
nol at 20 μL × min by micro flow HPLC syringe pump
Teledyne ISCO, Model 100DM). 20 μL of sample solution
(
Fig. 2 Explanation of the observed stereoselectivity in the palladium-catalyzed acetoxylation process (adopted from ref. 15).
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configurations of the new stereocenters was observed (i.e. attack
from top in Fig. 2) by NMR analysis.
Reducing the amount of oxidant (from two to one equivalents)
has only a marginal effect on the observed conversion and
selectivity. With regard to a more environmentally-friendly
acetoxylation process, this optimization constitutes a remark-
able improvement and clearly shows that an excess of the
oxidant is not necessary. However, if the amount of oxidant
was further decreased, the conversion significantly dropped.
Subsequent optimization studies were performed in order to
investigate the influence of the amount of solvent. According
to the above mentioned reaction screenings, 4 mol% of the
palladium catalyst and one equivalent of the oxidant were
used (Table 3).
These results are also in agreement with the results reported
by El Firdoussi et al., who employed (R)-(+)-limonene as substrate
for palladium-catalyzed oxidation using BQ and sodium acetate.
In this case, the internal acetoxylation occurred, which led to a
new stereocenter. Generally, the specific formation of these
enantiomers can be explained by coordination of the palla-
dium catalyst, which coordinates to the limonene substrate
via π-allyl and olefin bonding. The given stereo-configuration
of the limonene substrate enabled the formation of a palla-
dium complex, wherein the acetate can only attack from the
1
5
backside (Fig. 2). To optimize the catalytic oxidation of 1,
the amounts of palladium(II) acetate, BQ, DMSO, and acetic
acid were varied to yield a maximum conversion and product
selectivity. In order to minimize the catalyst loading, while
still obtaining high yields of 2, a first reaction screening was
performed (Table 1).
The catalyst loading was varied between 2 and 10 mol%.
No significant difference, both in conversion and in product
selectivity, was observed if the acetoxylation was performed
with 10 to 4 mol% (Table 1). However, if the amount of cata-
lyst was further reduced to 2 mol%, the conversion signifi-
cantly decreased. Based on these results, further studies were
carried out using 4 mol% of palladium(II) acetate. Since the
employed oxidant (BQ) is a toxic reagent and usually used in
excess, the next step was to try to reduce the required amount
of BQ (Table 2).
Generally, increasing the total amount of solvent (AcOH +
DMSO) from 1.0 mL to 3.0 mL has a positive effect on
the obtained conversion, without negatively influencing
the good product selectivity (Table 3). The dilution might
favor a stabilization of the active palladium species. However,
if one of the solvents was used in excess, either the con-
version or the product selectivity considerably decreased,
suggesting that an intermediate as depicted in Fig. 2 plays
indeed a key-role in this transformation. If an increased
amount of DMSO was used, lower conversions were observed
(Table 3, entry 5). Contrary, if an excess of acetic acid was
used, the conversion was slightly improved, but the product
selectivity decreased (Table 3, entry 6). As a further parameter,
the reaction temperature and its impact on the conversion
and product selectivity of the catalytic acetoxylation was inves-
tigated (Table 4).
Table 1 Results of the catalytic acetoxylation process of 1 using
different amounts of palladium catalyst
Table 3 Results of the catalytic acetoxylation of 1 using different
amounts of DMSO and acetic acid
a
Selectivity [%]
a
a
Selectivity [%]
AcOH
Entry [mL]
DMSO
[mL]
Conversion
[%]
a
Entry Catalyst [mol%] Conversion [%] 2 [%] 3/4 [%] 5/6 [%]
2 [%] 3/4 [%] 5/6 [%]
1
2
3
4
5
10
8
6
4
2
63
66
63
65
28
89
86
87
89
86
6
9
8
8
11
5
5
5
3
3
1
2
3
4
5
6
0.5
1.0
1.5
2.0
1.0
1.5
0.5
1.0
1.5
2.0
1.5
1.0
53
60
72
73
51
80
87
85
88
89
90
75
8
10
8
8
6
5
5
4
3
4
15
10
Conditions: 200 mg (1.47 mmol) 1, 1.0 mL acetic acid, 1.0 mL DMSO,
a
2.0 eq. BQ, 250 mg 3 Å molecular sieve, 50 °C, 24 h. Conversion and
Conditions: 200 mg (1.47 mmol) 1, 1.0 eq. BQ, 250 mg 3 Å
molecular sieve, 4.0 mol% Pd(OAc) , 50 °C, 24 h. Conversion and
2
selectivity were determined by GC-MS using tetradecane as internal
standard.
selectivity were determined by GC-MS using tetradecane as internal
standard.
a
Table 2 Results of the catalytic acetoxylation of 1 using different
amounts of para-benzoquinone and 4 mol% Pd(OAc)
2
Table
temperatures
4
Results of the catalytic acetoxylation of
1
at different
a
Selectivity [%]
a
Entry
BQ [eq.]
Conversion [%]
2 [%]
3/4 [%]
5/6 [%]
a
Selectivity [%]
1
2
3
4
5
2.0
1.5
1.0
0.5
0
64
63
60
44
12
89
83
85
86
50
6
9
10
11
25
5
8
5
3
25
a
Entry
T [°C]
Conversion [%]
2 [%]
3/4 [%]
5/6 [%]
1
2
3
50
60
70
72
72
73
88
85
81
8
11
13
4
4
6
Conditions: 200 mg (1.47 mmol) 1, 1.0 mL acetic acid, 1.0 mL
DMSO, 250 mg 3 Å molecular sieve, 4.0 mol% Pd(OAc) , 50 °C,
4 h. Conversion and selectivity were determined by GC-MS using
tetradecane as internal standard.
Conditions: 200 mg (1.47 mmol) 1, 1.5 mL acetic acid, 1.5 mL
DMSO, 1.0 eq. BQ, 250 mg molecular sieve, 4.0 mol%
, 24 h. Conversion and selectivity were determined by GC-MS
using tetradecane as internal standard.
2
3 Å
a
a
2
Pd(OAc)
2
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Table 6 Results of the Pd-catalyzed acetoxylation of 1 using DMSO
The obtained results revealed that increasing the tempera-
ture had no significant effect on the conversion, whereas the
product selectivity slightly decreased. Therefore, performing
the catalytic acetoxylation at 50 °C provided the most prom-
ising results. Applying the optimized reaction conditions to
a
Selectivity [%]
a
Entry
t [h]
Conversion [%]
2 [%]
3/4 [%]
5/6 [%]
1
2
3
5
6
2
4
6
24
48
7
13
23
73
91
72
77
70
85
86
28
23
22
10
10
0
(R)-(+)-limonene yielded similar conversions as well as the
8
5
4
same product selectivity. The remarkable selectivity, which
can be achieved in the catalytic acetoxylation using DMSO as
solvent, represents a highly efficient and promising proce-
dure. Moreover, to the best of our knowledge, these results
demonstrate the first direct catalytic acetoxylation (one-step)
of the exocyclic double bond of limonene. Further investiga-
tions were performed with some other polar aprotic solvents
in order to study their effect in the catalytic acetoxylation pro-
cess (Table 5).
Conditions: 200 mg (1.47 mmol) 1, 1.5 mL acetic acid, 1.5 mL
DMSO, 1.0 eq. BQ, 250 mg 3 Å molecular sieve, 4.0 mol% Pd(OAc) ,
2
a
5
0 °C. Conversion and selectivity were determined by GC-MS using
tetradecane as internal standard.
with a catalyst loading of 4 mol%, stoichiometric amounts
of BQ, DMSO/acetic acid as solvent in a 1 : 1 ratio at a temper-
ature of 50 °C. As shown in Table 6, increasing the reaction
time from 24 to 48 hours leads to almost full conversion with
this optimized system without compromising its selectivity.
To further reduce the environmental impact of this
acetoxylation procedure, we investigated acetoxylations of 1 using
an aerobic tandem catalytic system. The major advantage of this
catalytic procedure is the use of an ETM that is able to reoxidize
the employed oxidant (e.g. BQ). For this purpose, a coupled
system of palladium(II) acetate, hydroquinone (HQ) as oxidant
precursor, and iron(II) phthalocyanine (Fe(Pc), ETM) were used
in the presence of acetic acid and sodium acetate. In this case,
oxygen (air) is the primary oxidant. First reactions were carried
out using conditions reported by Bäckvall and co-workers for
Interestingly, depending on the used polar and aprotic
solvent, considerably different results were obtained. In reac-
tions using DMA or DMF as solvent, the catalytic acetoxylation
of 1 is highly promoted. However, mainly the functionalization
at the endocyclic double bond was observed, and almost
exclusively product 3 and 4 are formed. This is a very interest-
ing result and demonstrates that the product selectivity and
thus regioselectivity of this process can be inverted by simple
choice of solvent. If acetonitrile was used, only a low conver-
sion and product selectivity was observed. In a further test
reaction, tetrahydrothiophene (THT) was used as additive, since
Stambuli et al. described THT as highly reactive and selective
ligand in acetoxylation reactions to obtain (E)-linear allylic
2
0
acetates. Applying this catalytic process to 1, primarily the
endocyclic double bond of 1 was functionalized, thus the
enantiomers 3 and 4 as well as 5 and 6 were formed as major
products (Table 5, entry 4). However, THT is toxic and thus
replacing it with another additive, such as α,α,α-trifluorotoluene
21,22
the catalytic diacetoxylation of dienes (Fig. 3).
The obtained results of the aerobic process using 1 revealed
that very good conversions as well as a high selectivity can be
achieved. Since the applied catalyst highly promotes C–H acti-
vation at the endocyclic double bond, it enabled the forma-
tion of the enantiomers 3 and 4 as well as 5 and 6 as major
products. However, the acetoxylation also occurred at the exo-
cyclic double bond, and thus 2 was obtained as by-product.
Furthermore, with this catalytic system high conversions can
be obtained in shorter reaction times, if compared to the
aforementioned catalytic system involving DMSO (Table 7).
Additionally, the required amount of oxidant in the catalytic
aerobic process was tremendously reduced. Thus, a catalytic
amount of oxidant instead of stoichiometric amount is suffi-
cient to perform the acetoxylation in a very efficient manner.
Compared to the reaction conditions described above, the
aerobic oxidation process represents a notable improvement in
the development of a sustainable and environmentally-benign
catalytic acetoxylation procedure. Further studies were carried
out to investigate the effect of sodium acetate and DMSO as
an additive (Table 8).
(
PhCF ), was also investigated. Using PhCF3 instead of THT
3
under same reaction conditions, an almost quantitatively con-
version was achieved. In this case, the functionalization also
highly occurred at the endocyclic double bond. All in all, the
best results were obtained if the acetoxylation of 1 was performed
Table 5 Results of the catalytic acetoxylation of 1 using different solvents
c
Selectivity [%]
c
Entry
Solvent [x]
Conversion [%]
2 [%]
3/4 [%]
5/6 [%]
1
2
3
4
5
DMA
DMF
MeCN
84
81
30
78
96
11
16
47
6
51
37
32
50
52
38
47
21
44
41
a
THT
b
PhCF
3
5
Conditions: 200 mg (1.47 mmol) 1, 1.5 mL acetic acid, 1.5 mL
The obtained results show that the absence of sodium acetate
has no significant effect on conversion or selectivity. If DMSO
was added, a slightly lower conversion and improved selectivity
was observed, whereas the expected (see results above) selec-
tive formation of 2 was not achieved. Moreover, if an equiva-
lent amount of DMSO was used, only a very low conversion
x-solvent, 1.0 eq. BQ, 250 mg 3 Å molecular sieve, 4.0 mol%
a
Pd(OAc)
2
, 50 °C, 24 h. 136 mg (1.00 mmol) 1, 2.0 ml acetic acid,
b
2.0 eq. BQ, 5.0 mol% THT, 5.0 mol% Pd(OAc)
2
, 50 °C, 24 h. 136 mg
(
5
1.00 mmol) 1, 2.0 ml acetic acid, 2.0 eq. BQ, 5.0 mol% PhCF ,
.0 mol% Pd(OAc) , 50 °C, 24 h. Conversion and selectivity
2
3
c
were determined by GC-MS correlated using tetradecane as internal
standard.
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21,22
Fig. 3 Mechanism of the aerobic 1,4-diacetoxylation of 1,3-dienes using oxygen as primary oxidant.
Table 7 Results of the Pd-catalyzed acetoxylation of 1 using an aero-
bic tandem catalytic system
With respect to the established catalytic acetoxylation pro-
cesses, it would be very interesting to apply both acetoxylation
procedures sequentially in order to efficiently functionalize
the exo- and endocyclic double bond of 1 to obtain the respective
diacetoxylated products. Therefore, the mono-acetoxylated
products of 1 were used in further investigations. First the
mixture of enantiomers (3, 4, 5 and 6) obtained by the aerobic
tandem catalytic system was used for the acetoxylation process
using DMSO and stoichiometric amounts of BQ. After 48 hours
of reaction, no conversion was observed. Therefore, as a second
approach, the reverse strategy was tested (Fig. 4). Herein, the
product mixture obtained from the DMSO/BQ system was
used in the aerobic tandem catalytic acetoxylation procedure.
Indeed, the diacetoxylated products 7 and 8 as well as 9 and
a
Selectivity [%]
a
Entry
t [h]
Conversion [%]
2 [%]
3/4 [%]
5/6 [%]
1
2
3
4
2
4
6
39
69
78
98
—
8
9
39
36
37
33
61
56
54
57
24
10
Conditions: 200 mg (1.47 mmol) 1, 3.0 mL acetic acid, 0.5 eq.
sodium acetate, 20 mol% HQ, 5.0 mol% Fe(Pc), 5.0 mol% Pd(OAc)2′
,
a
6
0 °C, 24 h. Conversion and selectivity were determined by GC-MS
using tetradecane as internal standard.
1
0 were formed as respective enantiomers, although only a
Table 8 Results of the Pd-catalyzed acetoxylation of 1 using an modified
aerobic tandem catalytic system
moderate conversion of 45% was obtained after a reaction time
of 5 days. The presented sequential catalytic acetoxylation
process resulted in a product selectivity of 7 and 8 (72%) as
well as 9 and 10 (28%).
a
Selectivity [%]
a
Entry
Conversion [%]
2 [%]
3/4 [%]
5/6 [%]
The presented sequential diacetoxylation process is inter-
esting although the reaction conditions still need to be opti-
mized. However, this is the first catalytic two step procedure
to obtain the diacetoxylated products directly from limonene;
b
1
2
97
89
11
9
32
36
57
55
c
Conditions: 200 mg (1.47 mmol) 1, 3.0 mL acetic acid, 0.5 eq.
sodium acetate, 20 mol% HQ, 5.0 mol% Fe(Pc), 5.0 mol% Pd(OAc)2′
0 °C, 24 h. Conversion and selectivity were determined by GC-MS
using tetradecane as internal standard. Without sodium acetate.
0 mol% DMSO.
,
2
3
a
usually, longer reaction sequences are reported. Inter alia,
with such a diacetoxylation protocol, precursors for polycon-
densation reactions can be obtained. Simple saponification
leads to the corresponding diol compounds. Moreover, these
products as well as the mono-acetoxylated limonene are valu-
able precursors for transition metal catalyzed allylic substitu-
6
b
c
2
was obtained after 24 hours. Thus, DMSO might prevent the
reoxidation of the oxidant by the used ETM.
2
4,25
tion reactions.
Fig. 4 Diacetoxylation of 2 using the aerobic tandem catalytic system.
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6
7
E. A. Nonino, Perfum. Flavor., 1997, 22, 53–58.
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E. Breitmaier, in Terpenes: flavors, fragrances, pharmaca,
pheromones, GmbH & Co. KGaA, Wiley-VCH Verlag, 2006,
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The successful synthesis of regioselectively acetoxylated limo-
nene derivatives via two efficient catalytic systems is described.
The redox couple system of palladium(II) acetate/BQ using
DMSO and acetic acid as solvents enabled the acetoxylation of
limonene at the exocyclic double bond. The catalyst loading,
amount of oxidant, amount of solvent and temperature was
systematically optimized with regard to a maximum conver-
sion and product selectivity. Using the optimized reaction
conditions, good conversions as well as remarkable selectivity
were obtained. Additionally, some other polar and aprotic sol-
vents were investigated, which showed a different selectivity
to the aforementioned catalytic system using DMSO. On the
other hand by utilizing an aerobic tandem catalytic system of
palladium(II) acetate/hydroquinone/iron(II) phthalocyanine in
acetic as solvent, very good conversions and selectivities were
obtained. Herein, the substrate-selective catalyst highly pro-
moted the acetoxylation of limonene at the endocyclic double
bond. Furthermore, contrary to the redox coupled system, the
use of an ETM allowed for use of only catalytic amounts oxi-
dant (HQ). Thus, this catalytic system revealed to be highly
efficient and more environmentally benign due to the reduc-
tion the amount of toxic BQ, which is further supported by a
reduction of the E-factor by 1.4 (meaning 1.4 kg less waste are
produced per kg of product). Finally, both catalytic proce-
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tated the synthesis of diacetoxylated products and provide
access to various limonene derivatives.
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