A practical synthesis of d-α-terpineol via Markovnikov addition of d-limonene using trifluoroacetic acid

Article abstract of DOI:10.1021/op068012d

d-α-Terpineol (1), which is a useful flavor and fragrance compound, has been synthesized from d-limonene by Markovnikov addition using trifluoroacetic acid, followed by hydrolysis in 76% yield with 98% purity.

Full text of DOI:10.1021/op068012d

Organic Process Research & Development 2006, 10, 1231−1232
A Practical Synthesis of d-r-Terpineol via Markovnikov Addition of d-Limonene
Using Trifluoroacetic Acid
,
†
‡
Yoshifumi Yuasa* and Yoko Yuasa
Takasago International Corporation, 13 Sunayama, Kamisu, Ibaraki 314-0255, Japan, and School of Pharmacy,
Tokyo UniVersity of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Table 1. Results of solvent effecta,b
Abstract:
d-r-Terpineol (1), which is a useful flavor and fragrance
compound, has been synthesized from d-limonene by Mark-
ovnikov addition using trifluoroacetic acid, followed by hy-
drolysis in 76% yield with 98% purity.
solvent
conv (%) selectivity (%) yield of 1 (%)
1
2
cyclohexane
toluene
74
83
82
84
62
76
a
3 2
CO
H were used. b The conversion
0
.5 mol of d-limonene and 0.6 mol of CF
and selectivity were determined by GC.
Introduction
3 2
Table 2. Results of some variable amounts of CF CO
Ha-c
d-R-Terpineol (1) is a useful flavor and fragrance
1
-2
CF CO H
3
2
compound, for which many syntheses have been reported. d-
R-Pinene is used as a starting material in these methods;
however, it is difficult to obtain d-R-pinene in high chemical
and optical purity. Whereas d-limonene (2) is a readily
mol equiv
conv (%)
selectivity (%)
yield of 1 (%)
1
2
3
4
1.0
1.2
1.5
2.0
54
83
85
92
82
84
78
76
45
76
65
62
available material and some syntheses of d-R-terpineol from
d-limonene have been reported,3
-4
these reports are not
practical methods concerning the conversion, selectivity, and/
or yield.
a
.5 mol of d-limonene was used. b The reaction temperature was room
c
0
temperature, and toluene was used as the solvent.
were determined by GC.
The conversion and selectivity
On the other hand, Roberts published a kinetic study of
the reaction of limonene with trifluoroacetic acid, and d-R-
terpinyl trifluoroacetate (3) was characterized. Furthermore,
5
Scheme 1. Synthetic route of d-r-terpineol (1) from
d-limonene (2)a
Mattos has revisited this reaction using both enantiomers of
6
limonene. This compound 3, which was derived from
d-limonene by Markovnikov addition using trifluoroacetic
acid, can be readily introduced to 1 by hydrolysis. We have
re-examined this additional reaction of d-limonene with
trifluoroacetic acid on a kilogram scale and then the
hydrolysis of triflouroacetate 3. We now report the practical
and effective synthesis of 1 from 2 in order to provide a
stable supply of this flavor and fragrance chemical.
a
3 2
Reagents and conditions: (a) CF CO H, 20-30 °C, 4.5 h. (b) 20% NaOH-
O/MeOH, 20-30 °C, 2.5 h.
H
2
Results and Discussion
Initially, we attempted the addition reaction of d-limonene
or toluene as the solvent are shown in Table 1. The solvent
could be changed to toluene instead of cyclohexane. Next,
the amount of trifluoroacetic acid in toluene as the solvent
was investigated (Table 2). 1.2 mol equiv of trifluoroacetic
acid for 2 gave the best result (Table 2, run 2). Thus, the 1
kg scale of 2 was treated with 1.2 mol equiv of trifluoroacetic
acid in toluene at 20-30 °C for 4.5 h to give trifluoroacetate
3, which is not stable during column distillation for purifica-
tion but was stable during the Claisen-type distillation, and
then the crude 3 was hydrolyzed by 20%NaOHaq./methanol
solution at 20-30 °C for 2.5 h to quantitatively give 1
2
with trifluoroacetic acid according to the above-described
5
-6
literature.
The comparisons of the selectivity and the
6
isolated yield of 1 in cyclohexane using the literature method
*
To whom correspondence should be addressed. Telephone: 81-(0)479-46-
4
801. Fax: 81-(0)479-46-3310. E-mail: yoshifumi_yuasa@takasago.com.
†
Takasago International Corporation.
Tokyo University of Pharmacy and Life Science.
‡
(
(
(
(
1) Merkel, D. Die A¨ therischen O¨ len (Gildermeister-Hoffmann); Akademie-
Verlag: Berlin, 1962; Vol. IIIb, p 70.
2) Bukala, M.; Burczyk, B.; Kucharski, S.; Rulinska, J. Chem. Stosow., Ser.
A: 1968, 12, 371; Chem. Abs. 1969, 70, 68536.
3) Sakane, S.; Fujiwara, J.; Maruoka, K.; Yamamoto, H. Tetrahedron 1986,
4
2, 2193.
4) Nomura, M.; Kyoda, M.; Fujiwara, Y.; Tajima, K.; Otani, T. Yukagaku
994, 43, 1089.
(
Scheme 1). Purification of 1 by column distillation using
helipac no. 3 gave 1 with 98% purity in 76% isolated yield.
-Terpineol and cis-/trans-â-terpineol as byproducts have
1
(
(
5) Roberts, R. M. J. Chem. Soc., Perkin Trans. 2 1976, 1374.
6) de Mattos, M. C. S.; Coelho, R. B.; Sanseverino. Synth. Commun. 2004,
4
3
4, 541.
been estimated by GC-MS (Figure 1).
1
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Published on Web 10/24/2006

/
min; injection temperature, 230 °C, detector temperature,
2
2
50 °C. 2 t
, BC-Wax produced by GL Sciences, Inc., Japan, df ) 0.15
, 0.1 MPa, oven temperature,
00-230 °C programmed at 5 °C /min; injection tempera-
ture, 230 °C, detector temperature, 250 °C. 2 t , 3.2 min; 3
, 6.1 min; 1 t , 10.2 min (see Figure 1).
Scale-up Procedure of d-r-Terpineol (1). In a 10-L glass
vessel, toluene (2 L) and d-limonene [1068 g, 7.34 mol,
R R R
, 5.3 min; 1 t , 8.0 min; 3 t , 8.1 min. Column
µm, 0.25 mm ID; carrier gas N
1
2
R
t
R
R
2
3
6
20
9
6.7% purity, [R] ) +99.9° (neat), lit. [R] ) +118.7°
D D
(neat)] were added, and then trifluoroacetic acid (1,004 g,
8
.81mol) was dropwise added over 4 h at 20-30 °C. The
reaction mixture was stirred for 30 min, and water (4 L)
was added. The organic layer was separated and washed with
3
5%NaHCO solution (4 L) and then 5%NaCl solution (4 L).
After the solvent was recovered under reduced pressure (30
Torr, 50 °C), an oily residue (2,025 g) appeared. The residue
was dissolved in MeOH (2 L), and 20% NaOH solution
(
1600 g) was dropwise added for 1.5 h at 20-30 °C and
then the mixture was stirred for 1 h. A conc. HCl solution
360 g) and n-heptane (1.5 L) were added. The organic layer
(
Figure 1. GC chromatogram of distillate d-r-terpineol (1). GC
was separated and washed with water (4 L × 4). Solvent
was recovered under reduced pressure (30 Torr, 50 °C) to
give the crude product (1137 g) as a viscous oil, and then
the crude product was purified using a ten theoretical plate
conditions are described in the Experimental Section.
Experimental Section
All reagents and solvents were obtained from commercial
sources, except for d-limonene (Takasago), and used without
further purification. The boiling points are uncorrected
values. The NMR instrument was a Bruker DRX-500. The
GC was done using a Shimadzu GC-18A with an FID
detector (Column 1, Neutrabond-1 produced by GL Sciences,
column distillation with helipac no. 3 to give 1 (861.5 g,
7
7
1
6%, 98.2% purity). Bp 72 °C/4 Torr, 43 °C/0.1 Torr (lit.
04 °C/15 Torr). [R]D ) +81.7° (neat) [lit. [R]D
2
3
7
20
)
+100.5° (neat)]. The NMR data of the products are identical
with those in the literature.
Inc., Japan, df ) 0.15 µm, 0.25 mm ID; carrier gas N
2
, 0.1
MPa, oven temperature, 100-230 °C programmed at 5 °C
Received for review August 4, 2006.
OP068012D
(7) Dictionary of Organic Compounds, 6th ed.; Chapman & Hall: 1996.
1232
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Vol. 10, No. 6, 2006 / Organic Process Research & Development