A practical and efficient synthesis of p-menthane-3,8-diols

Article abstract of DOI:10.1021/op9901036

The diastereomeric repellents of p-menthane-3,8-diol were produced from citronellal by treatment with 0.25% sulfuric acid at 50°C for 11 h to give 97.9% conversion and 92.3% selectivity and citronellal acetal by-products with only 2.7%. The crude products were crystallized from n-heptane at -50°C for 20 h to give p-menthane-3,8-diols in 80% yield and high purity. The stereochemistry of the citronellal acetal by-products was determined by 2D NMR and NOE.

Full text of DOI:10.1021/op9901036

Organic Process Research & Development 2000, 4, 159−161
A Practical and Efficient Synthesis of p-Menthane-3,8-diols
,
†
†
‡
Yoshifumi Yuasa,* Haruki Tsuruta, and Yoko Yuasa
Technical Engineering Department, Takasago International Corporation, 1-5-1 Nishiyawata, Hiratsuka,
Kanagawa, 254-0073, Japan, and School of Pharmacy, Tokyo UniVersity of Pharmacy and Life Science,
1432-1 Horinouchi, Hachioji, 192-0335, Tokyo, Japan
Abstract:
Scheme 1. The cyclization of (+)-citronellal using dilute
sulfuric acid.
The diastereomeric repellents of p-menthane-3,8-diol were
produced from citronellal by treatment with 0.25% sulfuric acid
at 50 °C for 11 h to give 97.9% conversion and 92.3% selectivity
and citronellal acetal by-products with only 2.7%. The crude
products were crystallized from n-heptane at -50 °C for 20 h
to give p-menthane-3,8-diols in 80% yield and high purity. The
stereochemistry of the citronellal acetal by-products was
determined by 2D NMR and NOE.
Introduction
The p-menthane-3,8-diols (2) are naturally occurring
compounds. However, the cis- and trans-p-menthane-3,8-
diols in the form of racemic mixtures were obtained from
1
Eucalyptus citriodora by Nishimura et al. These compounds
are known to exert a repellent effect on insect pests such as
mosquitoes and fleas.2 It has been found that the cis isomer
-4
4
is more active than the trans isomer as an insect repellent.
6
two isomeric isopulegols as reaction products. Also, they
Zimmerman reported the synthesis of the cis (2a)- and trans
2b)- p-menthane-3,8-diols through acid-catalyzed cyclization
found a group of by-products with a molecular weight
substantially higher than that of 2. This group includes two
main components which are the citronellal acetals of 2.
(
5
of citronellal. Nishimura et al. also synthesized the (()-cis
and (()-trans isomers, however, they have not been reported
in detail.1
In this publication using (+)-citronellal (1) as starting
material and by treatment of a sulfuric acid aqueous solution
5-9%) for 27 h at room temperature (Scheme 1), the cis/
trans p-menthane-3,8-diols were obtained in a ratio of about
:1-5:2. These compounds were obtained in pure form after
chromatographic separation and recrystallization. However,
the reported acid-catalyzed cyclization of 1 produced a
mixture of 40-45% cis- and 60-55% trans-p-menthane-
7,8
Each of these components comprise a mixture of two
diastereomeric compounds that are epimeric at the acetal
carbon.
After acid-catalyzed cyclization of 1, the reaction mixture
contains about 15-20% low-boiling materials (including
citronellal), about 50-60% p-menthane-3,8-diols and 20%
acetals. This purity and yield of the p-menthane-3,8-diols 2
are not sufficient for large-scale production. For this reason,
we investigated the sulfuric acid-catalyzed cyclization of
(
2
9
citronellal more closely.
3,8-diols 2. Furthermore, Clark et al., have investigated the
reaction rate enhancement and stereochemical course of the
Results and Discussion
acid-catalyzed cyclization of 1 to 2a and 2b. They identified
We investigated the parameters concentration (H SO ),
2
4
reaction temperature, and reaction time. The results are
shown in Table 1. Conversion of (+)-citronellal, selectivity
torwards the p-menthane-3,8-diols (cis/trans mixture) and
the production rate of the acetals were measured by gas
chromatography (Figure 1). Peaks 6 and 8 could not be
*
To whom correspondence should be addressed. Telephone: 81-(0)463-21-
7
150. Fax: 81-(0)463-23-1655. E-mail: TIC00488@niftyserve.ne.jp.
†
Takasago International Corporation.
Tokyo University of Pharmacy and Life Science.
‡
(
(
(
(
(
1) Nishimura, H.; Kaku, K.; Nakamura, T.; Fukazawa, Y.; Mizutani, J. Agric.
Biol. Chem. 1982, 46 (1), 319-320.
2) Nishimura, H.; Kobayashi, K.; Unno, T. Jpn. Kokai Tokkyo Koho
JP60199804, 1985; Chem. Abstr. 1986, 104, 83820g.
3) Kobayashi, M.; Yamamoto, Y. Jpn. Kokai Tokkyo Koho JP03133906, 1991;
Chem. Abstr. 1991, 115, 226183s.
(6) Clark, B. C., Jr.; Chamblee, T. S.; Iacobucci, G. A. J. Org. Chem. 1984,
49, 4557-4559.
(7) Stoll, M.; Bolle, P. HelV. Chim. Acta 1948, 31, 1-4.
(8) Naves, Y.-R.; Ochsner, P. HelV. Chim. Acta 1964, 47, 51-66.
(9) This work has appeared in preliminary form: Kenmochi, H.; Akiyama,
T.; Yuasa, Y.; Kobayashi, T.; Tachikawa, A. Jpn. Kokai Tokkyo Koho
JP11130710, 1999; Chem. Abstr. 1999, 131, 5396s.
4) Lett, B. D.; Kraus, H. S. PCT Int. Appl. WO9202136, 1992; Chem. Abstr.
1
992, 117, 2827h.
5) Zimmerman, H. E.; English, J., Jr. J. Am. Chem. Soc. 1953, 75, 2367-
370.
2
1
0.1021/op9901036 CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Vol. 4, No. 3, 2000 / Organic Process Research & Development
•
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Published on Web 03/18/2000

Table 1. Influence of various concentrations of sulfuric acid
a
upon the cyclization of (+)-citronellal )
low
concd
SO
boiling select.d select.d yielde
H
2
4
temp. time conv. compdsc of 2
of 3
of 2
b
run (%)
(°C) (%) (%)
(%)
(%)
(%)
(%)
1
2
3
4
5
6
7
8
9
0
1
2
3
10
5
3
1
0.5
0.25
0.25
0.25
0.15
0.05
0.05 100
0.02 100
0.01 100
35
35
35
25
25
50
60
70
60
60
4
6
6
97.1
98.9
98.3
5.9
5.5
6.3
20.5
5.7
5.0
5.7
6.3
6.4
7.9
73.8
72.0
78.8
72.0
89.5
92.3
91.5
90.1
91.7
91.0
87.7
87.4
80.8
20.3
22.5
14.9
7.5
4.8
2.7
2.8
3.6
1.9
1.1
2.0
1.5
2.7
63
62
69
61
75
79
80
78
78
76
75
75
70
16 96.9
20 95.3
11 97.9
7
6
10 97.8
20 95.4
5
Figure 2. Important NOEs for 3a and 3b.
In addition, the cyclization in run 13 was slow and the
selectivity lower despite the long reaction time and high
temperature (100 °C) due to the very low concentration of
sulfuric acid (0.01%).
The best yields of 2 were obtained in the temperature
range of 50-60°. The reaction mixture is extracted with an
organic solvent and distilled in vacuo directly. However, the
acetals 3 cannot be separated from the p-menthane-3,8-diol
by distillation, therefore, it is difficult to obtain 2 in high
purity.
98.2
99.0
1
1
1
1
98.7
10.3
11.1
16.5
10 97.4
20 97.5
a
b
Conversion and selectivty determined by GC. Concentration of sulfuric
acid aqueous solution is in wt %. c The low-boiling point compounds are
d
citronellal, neoisopulegol, isopulegol, and an unknown compound. The percent-
ages of 2 and 3 consist of the 2 isomers and 3 isomers, respectively. e Isolated
yield of 2.
A solution of this problem was crystallization at low
temperature. Thus, the reaction mixture was extracted with
n-heptane, and the organic phase was cooled at -50 °C for
2
0 h to precipitate 2 as crystals. This was quickly followed
by filtration using a centrifuge. The crystals were distilled
for complete removal of n-heptane to give 2 in 80% isolated
yield (purity: 99%). The cis/trans ratio had changed only
slightly (see Experimental Section). Using toluene as a
solvent, the crystallization of 2 was difficult. The Experi-
mental Section shows the optimal conditions and results for
runs 6 and 7 on a 500 g scale. Moreover, we succeeded in
the separation of the two diastereomer acetals 3 by silica
gel column chromatography. The structures of 3a and 3b
were determined by 2D-NMR and nuclear Overhauser effect-
(
NOE), respectively. Thus, evidence for the cis relation
between two methine protons in the dioxane ring of 3a and
b were given by enhancement of the H-1′ (acetal) resonance
3
upon irradiation of H-3 (Figure 2). The other diastereomeric
acetals were only present in very small amounts and therefore
not isolated, but were assumed to be the acetals of 2c and
2
d. In a pilot plant, we have already produced 100 kg of
p-menthane-3,8-diol by using the above-described sulfuric
acid catalysis and the crystallization method at low temper-
atures.
In the future, p-menthane-3,8-diol 2 will be produced on
a a 5-ton scale by our corporation.
Figure 1. GC chromatogram of the cyclization products of
citronellal using sulfuric acid. Reaction and GC conditions are
described in the Experimental Section.
Experimental Section
All reagents and solvents were obtained from commercial
sources and used without further purification. IR spectra were
recorded on a Jasco IR-810, NMR spectra on a Bruker AM-
isolated but were determined to be compounds 2c and 2d,
respectively (GC/MS). When the p-menthane-3,8-diols 2
were produced by treatment of (+)-citronellal with 0.25%
sulfuric acid at 50 °C for 11 h to give the citronellal, acetal
by-products 3 are as low as 2.7%, whereas conversion and
the selectivity to give 2 reach 97.9 and 92.3%(cis/trans )
1
13
4
00. H and C spectra were determined at 400 and 100
MHz, respectively, and were recorded in CDCl with TMS
3
as the internal standard. The chemical shifts were given in
δ (ppm).
MS: Hitachi M-80A mass spectrometer at 70 eV.
Optical rotations: Jasco DIP-4 digital polarimeter.
GC: Shimadzu GC-14A with an FID detector. Column:
Neutrabond-1 (df ) 0.15 µm, 0.25 mm ID × 30m, available
63.6:36.4), respectively.
On the other hand, in the experiments of runs 1 and 2,
acetals 3 were produced with more than 20%, consequently,
6
the experiments described in the literature are reproducible.
160
•
Vol. 4, No. 3, 2000 / Organic Process Research & Development

from GL Science Inc., Japan); carrier gas N
temperature, 100-250 °C programmed at 10°/min; injection
and detector temperatures, 250 °C.
2
, 0.1 Mpa; oven
31.2 (CH), 34.5 (CH
74.8 (C). EI-MS (m/e, relative intensity) 157(M - 15, 4),
154 (2), 139 (9),121 (6), 111 (4), 96 (49), 81 (100), 67 (18),
2
), 44.4 (CH
2
), 53.0 (CH), 72.6 (CH),
+
Column chromatography: Merck Kieselgel60, Art.-
No.7734.
59 (79), 54 (25), 43 (16). Anal. Calcd for C10
69.72; H, 11.70. Found: C, 69.62, H, 11.80.
20 2
H O : C,
Melting points: Yanagimoto micro melting apparatus,
uncorrected values.
Boiling points: uncorrected values.
Synthesis of p-Menthane-3,8-diols (2). In a 3-L round-
bottomed flask 636 g (16.3 mmol; 0.5 mol %) of a 0.25 wt
The mother liquor of recrystallized 2 was concentrated
in vacuo and purified by column chromatography (silica gel,
eluent: ethyl acetate/n-hexane ) 1:20) to give the cis form
and the trans form of the p-menthane-3,8-diol citronellal
acetals 3 separately.
%
5
(
sulfuric acid aqueous solution was charged and heated at
5 °C with stirring. (+)-Citronellal 1 (500 g, 3.24 mol)
produced by Takasago Int. Corp., 98.6% and 96% ee) was
Spectral data of cis-p-menthane-3,8-diol citronellal
2
3
acetal (3a): bp 123-127 °C/ 0.2 Torr., [R]
) 1.08, CHCl ). IR (neat) ν ) 2950, 1455, 1380 cm . H
NMR 0.82-0.95 (m, 1H), 0.84 (d, J ) 6.4 Hz, 3H, CH ),
0.89 (d, J ) 6.6 Hz, 3H, CH ), 0.98-1.06 (m, 1H), 1.13-
1.19 (m, 1H), 1.12 and 1.32 (each s, 3H, ring C(CH ),
1.32-1.40 (m, 3H), 1.54-1.62 (m, 1H), 1.66-1.75 (m, 4H),
1.59 and 1.68 (each s, 3H, dC(CH ), 1.87-2.03 (m, 3H),
4.09 (brs, 1H, -CH-O), 4.87 (t, J ) 4.3 Hz, 1H, O-CH-
D
) -8.33° (c
-
1 1
3
added dropwise over 1 h. The reaction mixture was main-
tained at 55 °C for 10 h. Conversion of 1 and selectivity of
2
3
3
were 99.0 and 92.3% (2a/2c/2b/2d ) 61.2/1.2/35.0/2.6)
3 2
)
by GC, respectively. Acetals 3 (2.1%) were detected as well.
Then 8 g (50 mmol) of an aqueous 25 wt % sodium
hydroxide solution were added, followed by addition of 1200
mL of n-heptane. The organic layer was washed with 500
mL of water, separated, and refluxed to separate the water
azeotropically. The organic solution was cooled to -50 °C
and stirred for 20 h at this temperature. The colorless
crystalline 2 was filtered using a centrifuge. The crystalline
3 2
)
13
O), 5.08-5.12 (m,1H, -CHdC(Me)
19.6 (CH ), 22.1 (CH ), 22.3 (CH ), 23.5 (CH
), 25.9 (CH), 27.7 (CH ), 28.3 (CH), 34.4 (CH
), 40.6 (CH ), 41.5 (CH), 42.3 (CH ), 71.0 (CH),
2
). C NMR 17.6 (CH
3
),
),
),
3
2
3
3
), 25.3 (CH
2
25.7 (CH
37.5 (CH
3
3
2
2
2
2
73.5 (C), 94.4 (CH), 125.0 (CH), 130.9 (C). EI-MS (m/e,
+
+
2
was distilled to yield 447 g (80%) of the p-menthane-3,8-
diols 2. (The boiling point of the mixture 2 was 100-130
C/0.8 Torr.) The distilled oily product crystallizes at 30 °C
again. The purity of the diastereomeric mixture 2 was 99.5%
2a/2c/2b/2d ) 64.7/0.2/ 34.0/1.1); only 0.15% of the acetals
were detected (GC). Other impurities: 0.1% of citronellal
relative intensity) 308 (M , 2), 307 (M - 1, 5), 290 (6),
250 (6), 223 (8), 205 (11), 183 (28), 154 (93), 137 (100),
121 (32), 112 (42), 95 (32), 81 (89), 69 (9). HRMS calcd
°
for C20H O
36 2
: 308.5032; found: 308.5031.
(
3
Spectral data of trans-p-menthane-3,8-diol citronellal
2
3
acetal (3b): bp 125-128 °C/0.2Torr., [R]
) 1.06, CHCl ). IR (neat) ν ) 2930, 1455, 1380 cm . H
NMR 0.86-0.89 (m, 3H), 0.90 (d, J ) 6.7 Hz, 3H, CH ),
0.93 (d, J ) 6.6 Hz, 3H, CH ), 1.14-1.16 (m, 3H), 1.19
and 1.21 (each s, 3H, ring C(CH ), 1.32-1.40 (m, 3H,),
1.40-1.53 (m, 1H), 1.56-1.61 (m, 1H), 1.66-1.70 (m, 1H),
1.59 and 1.67 (each s, 3H, dC(CH ), 1.90-2.04 (m, 3H),
3.43 (dq, J ) 8.2, 4.1 Hz, 1H, -CH-O), 4.87 (t, J ) 5.5
D
) +19.81° (c
-
1 1
and 0.25% of neoisopulegol and isopulegol; 25 g of the
p-menthane-3,8-diols 2 obtained by the above-mentioned
method were purified by column chromatography (silica gel
3
3
3
300 g, eluent: ethyl acetate/n-hexane ) 1: 5) to give 5.2 g
3 2
)
of the cis form 2a and 3.5 g of the trans form 2b.
Spectral data of cis-p-menthane-3,8-diol (2a): mp 67
3 2
)
2
0
°
C, [R]
D
) +15.4° (c ) 0.5, CHCl
3
). IR(KBr) ν ) 3260
-
1 1
cm . H NMR 0.86-0.96 (m, 1H), 0.87 (d, J ) 6 Hz, 3H,
CH
CH
Hz, 1H, O-CH-O), 5.08-5.13 (m, 1H, -CHdC(Me)
2
).
),
1
3
3
), 1.05 (t, 9 Hz, 1H,), 1.13-1.18 (m, 1H), 1.22 (s, 3H,
), 1.36 (s, 3H, CH ), 1.64-1.86 (m, 5H), 2.97 (s, 1H),
C NMR 18.3 (CH
25.9 (CH X2), 26.0 (CH
35.4 (CH ), 37.9 (CH ), 41.6 (CH
75. 2(C), 75.7 (CH), 94.8 (CH), 125.6 (CH), 131.7 (C). EI-
3
), 19.4 (CH
), 29.1 (CH), 29.7 (CH
), 43.1 (CH
3 3
), 20.4 (CH ), 22.9 (CH
3
3
3
2
3
3
), 31.9 (CH),
2
), 50.5 (CH),
13
3.25 (d, J ) 2 Hz, 1H,), 4.40 (brs, 1H). C NMR 20.3 (CH
22.2 (CH ), 25.6 (CH), 28.7 (CH ), 28.9 (CH ), 34.9 (CH
42.5 (CH ), 48.3 (CH), 67.9 (CH), 73.2 (C). EI-MS (m/e,
2
),
2
2
2
3
3
3
2
),
+
+
2
MS (m/e, relative intensity) 308 (M , 1), 307 (M - 1, 3),
306 (6), 289 (4), 249 (6), 222 (12), 182 (40), 154 (84), 137
(100), 121 (27), 111 (34), 95 (47), 81 (94), 69 (33), 59 (26),
+
+
relative intensity) 157 (M -15, 4), 154 (M -18, 5), 139 (11),
1
4
21 (9), 111 (7), 96 (53), 81 (100), 67 (18), 59 (62), 54 (23),
3 (34). Anal. Calcd for C10 : C, 69.72; H, 11.70.
H
20
O
2
36 2
43 (67). HRMS calcd for C20H O : 308.5032; found:
Found: C, 69.65, H, 11.79.
Spectral data of trans-p-menthane-3,8-diol (2b): mp.
308.5033.
2
0
Acknowledgment
We are grateful to Mr. Hiroyuki Kenmoch and Mr.
Teruyoshi Akiyama for their skillful technical assistance.
7
3
3 °C, [R]
D
) -14.4°, (c ) 0.5, CHCl
3
). IR(KBr) ν )
260 cm . H NMR 0.84-0.98 (m, 2H), 0.92 (d, J ) 6.5
), 1.04 (q, J ) 11, 24 Hz, 1H), 1.22 (s, 6H,
), 1.35-1.49 (m, 2H), 1.63-1.73 (m, 2H), 1.92-1.97
m, 1H), 3.71 (m, 1H), 3.95 (s, 1H), 4.21 (d, J ) 3 Hz, 1H).
-
1
1
Hz, 3H, CH
CH
3
3
Received for review November 29, 1999.
OP9901036
(
1
3
3 3 2 3
C NMR 21.9 (CH ), 23.5 (CH ), 26.9 (CH ), 29.7 (CH ),
Vol. 4, No. 3, 2000 / Organic Process Research & Development
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