A chromium-free synthesis of enantiopure 5-oxoborneol

Article abstract of DOI:10.1016/j.tetlet.2011.06.076

Enantiopure (-)-5-oxoborneol was obtained in 35% overall yield in two steps, starting from readily available (-)-bornyl acetate and using oxone as a safe and inexpensive oxidant. The reported procedure avoids the use of large excess of noxious chromium(VI), which was required by the so far reported syntheses.

Full text of DOI:10.1016/j.tetlet.2011.06.076

Tetrahedron Letters 52 (2011) 4478–4480
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A chromium-free synthesis of enantiopure 5-oxoborneol
⇑
Stefano Tartaggia, Pierluigi Padovan, Giuseppe Borsato, Ottorino De Lucchi, Fabrizio Fabris
Dipartimento di Scienze Molecolari e Nanosistemi, Università Ca’ Foscari di Venezia, Dorsoduro 2137, I-30123 Venezia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiopure (ꢀ)-5-oxoborneol was obtained in 35% overall yield in two steps, starting from readily avail-
able (ꢀ)-bornyl acetate and using oxoneÒ as a safe and inexpensive oxidant. The reported procedure
avoids the use of large excess of noxious chromium(VI), which was required by the so far reported
syntheses.
Received 25 May 2011
Revised 14 June 2011
Accepted 17 June 2011
Available online 25 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Borneol
Camphor
Catalysis
Oxidation
OxoneÒ
Ruthenium
Terpene
Terpenes are a natural-occurring source of inexpensive enantio-
pure starting material for the preparation of many important
chemicals, such as chiral auxiliaries, pharmaceuticals, pesticides,
cosmetics, and fragrances. A key step for practical applications is
the introduction in well-defined positions of further functional
groups in the skeleton of the molecule. These transformations are
not always trivial, especially considering the oxidation of saturated
carbons,1 which often results with unpredictable results.
final outcome (Table 1, entry 3). Although ruthenium(VIII) cannot
be considered a safe reagent, its use in catalytic amounts consider-
ably reduces the risk and the environmental impact.12 In this case,
a proper co-oxidant (unreactive with the substrate or the products)
and a suitable solvent system (to stabilize intermediates) are re-
quired. Many oxidants were tested, among them, gaseous ozone13
was considered the most convenient, because its excess, as well as
its by-products, can be easily removed from the reaction mixture.
Disappointedly, when the stream of O2/O3 passed through the
reaction mixture, it removed the volatile ruthenium(VIII) oxide,
leaving the starting material unchanged (Table 1, entry 4).
Peroxides are a convenient class of oxidants, which produce
relatively safe by-products (water in the case of hydrogen perox-
ide), and effectively promote the formation of Ru(VIII) in the cat-
alytic cycle.12 Hydrogen peroxide14 was mostly converted into
oxygen in the presence of RuCl3, as witnessed by copious foam-
ing, and it afforded very low and erratic yields of 5-oxobornyl
acetate 1 (Table 1, entry 5).
Our research, aimed at the synthesis of enantiomerically pure
cyclotrimers,2 is based on the availability of enantiomerically pure
5-oxoborneol 2, which has also been employed for the synthesis of
drugs,3 functionalized polymers,4 fragrances,5 chemical–physical
studies6, and as a substrate for biological transformations.7 This
compound has always been prepared by oxidation of (ꢀ)-bornyl
acetate with a large excess of chromium(VI) oxide in different sol-
vents,8 affording (ꢀ)-5-oxobornyl acetate 1, which is hydrolyzed
under basic conditions (Scheme 1). In order to avoid the use of
large amounts of noxious and environmentally hazardous chro-
mium(VI) (Table 1, entries 1 and 2), an alternative procedure was
studied upon screening a number of oxidation procedures for
(ꢀ)-bornyl acetate, which are herein described.
Slightly better results were obtained with tert-butyl hydroper-
oxide,15 which was slowly added to the reagent as an 80% solution
in di-tert-butylperoxide/water (3:2), causing evolution of heat,
The first oxidant tested was the inexpensive and environmen-
tally friendly N-hydroxyphthalimide (NHPI), which is known to
promote oxidation of unactivated alkanes under very mild condi-
tions.9 This reagent left bornyl acetate unaltered, and the introduc-
tion of additives (e.g., cobalt(II)10 or TBABr11) did not change the
hydrolysis
CrO3
(90-95% yield)
AcOH or
AcOH/Ac2O
(15-42% yield)
ref. 8
OAc
OH
OAc
O
O
(-)-bornyl acetate
1
2
⇑
Corresponding author.
E-mail address: fabrisfa@unive.it (F. Fabris).
Scheme 1. Common procedure for the preparation of 5-oxoborneol 2.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.076

S. Tartaggia et al. / Tetrahedron Letters 52 (2011) 4478–4480
4479
Table 1
Reagents and yields for the oxidation of bornyl acetate to afford 5-oxobornyl acetate 1
Entry
Oxidant
Ox. Eq.
Catalyst
Cat. Eq.
Solvent
Temp
Time
Yield
1
2
3
4
5
6
7
8
9
CrO3
CrO3
O2
O3
2.9
5.6
(1.0 bar)
(0.1 bar)
20
40
2.0
1.8
3.5
—
—
—
—
Ac2O/AcOH
AcOH
AcOH
AcOH/H2O
AcOH/AcOEt
(t-BuO)2/t-H2O
MeCN/AcOH/H2O
MeCN/AcOH/H2O
MeCN/AcOH/H2O
25 °C
140 °C
100 °C
25 °C
50 °C
70 °C
60 °C
60 °C
25 °C
170 h
5 h
18 h
6 h
4 h
2 h
24 h
45 h
4 h
32–42%12
15–35%12
—
NHPI
RuCl3
RuCl3
RuCl3
RuCl3
RuCl3
RuCl3
0.10
0.05
0.05
0.05
0.02
0.02
0.01
—
H2O2
0–3%a
4%a
t-BuOOH
Ca(ClO)2
NaIO4
OxoneÒ
8%a
19%b
35%c
a
b
c
Nonisolated yield (GC).
Isolated yield.
Isolated yield after the hydrolysis of acetate.
which serves to distill the tert-butanol, produced along the reac-
tion. The conversion of bornyl acetate ceased after the addition
of nearly 40 equiv of tert-BuOOH, affording complex mixtures of
products, in which 1 was detected in modest amounts (Table 1,
entry 6).
Hypochlorites are inexpensive reagents, which are suitable for
ruthenium catalyzed oxidations of alkanes.16 Calcium hypochlorite
furnished crude materials containing unreacted acetyl borneol, the
expected 5-oxobornyl acetate 1 and many chlorinated by-products
(Table 1, entry 7). These compounds were presumably derived
from the reaction of reagent and products with chlorine generated
by the dismutation of hypochlorous acid (HClO) arising from the
interaction of acetic acid and hypochlorite ion. Substitution of ace-
tic acid with dichloromethane almost suppressed reactivity even at
60 °C.
to notice that 3-oxobornyl acetate 3 was converted into a water-
soluble derivative, which could be readily separated from the de-
sired (ꢀ)-5-oxoborneol (Scheme 2).
In conclusion, although ruthenium(VIII) oxide is not a ‘green’ re-
agent, the low amount (1 mol %) required for the reaction could
compensate its toxicity, especially in consideration of the original
procedures. An added advantage of the present method is the ease
of separation and recovery of the desired product after saponifica-
tion. The expected (ꢀ)-5-oxoborneol 2 is hence obtained in a
reproducible 35% overall yield after crystallization from hot
cyclohexane.
Experimental
(ꢀ)-Bornyl acetate (14 mL, 13.7 g, 70.0 mmol), a mixture of
Sodium periodate17 can be considered an expensive reagent,
but it was tested as an oxidant in ruthenium catalyzed oxidation
of bornyl acetate. The best compromise between selectivity and
reactivity was found while carrying out the reaction at 60 °C for
45 h in a ternary solvent (AcOH/MeCN/H2O) with RuCl3 as the
pre-catalyst (2 mol %), to afford a partially converted (10% unre-
acted bornyl acetate) mixture of camphor (25%), 2,5-bornanedione
4 (9%) and 5-oxobornyl acetate 1 (16% yield) (Table 1, entry 8).
Eventually, inexpensive and readily available oxoneÒ
(2KHSO5ꢁKHSO4ꢁK2SO4)18 afforded a complete conversion of bornyl
acetate and acceptable selectivity. The reaction was best per-
formed with 1 mol % of ruthenium and 3.5 equiv of oxoneÒ and
did not require external heating. Indeed, the controlled spontane-
ous exothermicity sufficed to lead the reaction to completion (Ta-
ble 1, entry 9). Analysis of the crude mixtures (GC–MS, 1H NMR)
displayed the formation of the expected 5-oxobornyl acetate 1
(37% yield) and the isomeric 3-oxobornyl acetate 3 (10% yield),
concomitantly with minor amounts of borneol and 2,5-bornanedi-
one 4 (10% combined yields) (Scheme 2).
MeCN/AcOH/H2O (1:1:1.4, 155 mL), oxoneÒ (150.0 g, 244 mmol)
19
and a 0.1 M aq solution of RuO4 (7 mL) were added in sequence
in a 500 mL screw-capped Schott DuranÒ bottle. The bottle was
carefully sealed and placed in a bucket20 containing water at room
temperature, enough to fit the level of the reaction mixture (nearly
2 L). The slurry was maintained under vigorous stirring for 4 h,
during which heat and oxygen evolved and pressure increased.
The end-point of the reaction was monitored by the change of color
from bright yellow to light brown. The bottle was cautiously
opened (dissolved oxygen in the liquid can cause foaming) and
the resulting slurry was filtered, washing the inorganic salts with
AcOEt (3 ꢂ 50 mL). The aqueous layer was diluted with H2O
(100 mL) and extracted with AcOEt (3 ꢂ 50 mL). Combined organic
washing and extracts were placed into a 1 L beaker and cautiously
neutralized adding solid Na2CO3, then the mixture was filtered and
the organic layer dried over MgSO4 and concentrated under re-
duced pressure. The resulting oil was dissolved in EtOH (70 mL)
and KOH (3.92 g, 70.0 mmol) was added. The resulting solution
was stirred at rt under Ar for 4 h. Volatile materials were removed
under reduced pressure, the residue was diluted in satd aq NaCl
(100 mL) and extracted with Et2O (3 ꢂ 50 mL). Combined organic
layers were dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by re-crystallization from hot
cyclohexane to afford 3.76 g of 2 (32% yield)21 as pale yellow crys-
Since the large scale (fractional distillation or crystallization)
separations of 1 from 3 proved to be not possible, the crude mate-
rial of the oxidation step was directly hydrolyzed. We were pleased
tals, mp 235–237 °C (lit.8 239–241 °C); ½a D22
ꢃ
ꢀ86 (c 1.1, CHCl3) (lit.8
oxone
RuCl3 (1% mol)
ꢀ74 (c 1.6, CHCl3)); 1H NMR (CDCl3, 200 MHz) d (ppm): 4.42 (1H,
ddd, J = 9.6, 3.7 and 1.8 Hz), 2.64 (1H, d, J = 18.7 Hz), 2.51 (1H,
ddd, J = 14.4, 9.6 and 5.3 Hz), 2.14 (1H, d, J = 5.3 Hz), 1.91 (1H,
ddd, J = 18.7 and 1.8 Hz), 1.60 (1H, br s), 1.31 (1H, dd, J = 14.4
and 3.7 Hz), 1.03 (3 H, s), 0.98 (3 H, s), 0.94 (3 H, s).
+
+
O
AcOH/MeCN/H2O
OAc
OAc
1 (37%)
OAc
O
O
O
(-)-bornyl acetate
3 (10%)
4 (5-7%)
NaOH
EtOH
OH
O
Acknowledgment
2
(35% for two steps)
This work was co-founded by MIUR (Rome) within the national
PRIN framework.
Scheme 2. Ruthenium(VIII) catalyzed oxidation of (ꢀ)-bornyl acetate and hydro-
lysis to afford (ꢀ)-5-oxoborneol 2.

4480
S. Tartaggia et al. / Tetrahedron Letters 52 (2011) 4478–4480
33, 99–105; Biotransformations with different microorganisms (an
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