A Novel Route to trans-Epoxidation of Terpinen-4-ol

Article abstract of DOI:10.1007/s00706-003-0107-0

Pure (1S,2R,4S)-1,2-epoxy-p-menthan-4-ol and (1R,2S,4R)-1,2-epoxy-p- menthan-4-ol (trans-epoxides of (4S)-terpinen-4-ol and (4R)-terpinen-4-ol) were prepared and certain reactions of these compounds with nucleophilic reagents were studied. It was shown th

Full text of DOI:10.1007/s00706-003-0107-0

Monatshefte f€ur Chemie 135, 35–40 (2004)
DOI 10.1007/s00706-003-0107-0
A Novel Route to trans-Epoxidation
of Terpinen-4-ol
1;2
1
2;ꢀ
€
Erika Kozma , Ioan Cristea , and Norbert Muller
1
Department of Organic Chemistry, Babes-Bolyai University, Cluj-Napoca, Romania
2
Institute of Chemistry=Organic Chemistry, Johannes Kepler University, Linz, Austria
Received August 27, 2003; accepted September 1, 2003
Published online November 20, 2003 # Springer-Verlag 2003
Summary. Pure (1S,2R,4S)-1,2-epoxy-p-menthan-4-ol and (1R,2S,4R)-1,2-epoxy-p-menthan-4-ol
(trans-epoxides of (4S)-terpinen-4-ol and (4R)-terpinen-4-ol) were prepared and certain reactions of
these compounds with nucleophilic reagents were studied. It was shown that the F€urst-Plattner rule
regarding the trans-diaxial opening of cyclohexene epoxides predicts the predominant products in all
cases studied.
Keywords. Terpinen-4-ol; trans-Epoxidation; Tosylation; Acetylation.
Introduction
Oxiranes (epoxides) are compounds which are widely distributed in nature and are
of industrial, mechanistic, and biochemical interest. The ease of preparation of
epoxides and their facile ring opening have made them important intermediates
in organic chemistry for the past several decades. Presently the main objective in
organic synthesis is to develop reactions which are enantio-, diastereo-, regio-, and
chemoselective.
The epoxidation of an unsaturated substrate may be achieved by treatment with
different peroxycarboxylic acids. Oxidation of terpinen-4-ol with buffered perace-
tic acid [1] gave the two epoxides, cis:trans ¼ 7:3, which were separated by g.l.c.
and oxidation with peroxylauric acid in chloroform gave the two epoxides in the
ratio 3:2 [1, 2].
We developed a new regio- and stereoselective method for the preparation of
(1S,2R,4S)-1,2-epoxy-p-menthan-4-ol (3a) and (1R,2S,4R)-1,2-epoxy-p-menthan-
4-ol (3b) which consists of a two step process: a regioselective tosylation followed
by nucleophilic substitution, which leads to trans-epoxides. The structures of the
obtained trans-epoxides were determined by spectroscopical analysis and chemical
reactions.
ꢀ
Corresponding author. E-mail: Norbert.Mueller@jk.uni-linz.ac.at

36
E. Kozma et al.
Results and Discussions
The starting materials (1S,2S,4S)-p-menthane-1,2,4-triol (1a) and (1R,2R,4R)-p-
menthane-1,2,4-triol (1b) were obtained by trans-dihydroxylation of (4S)- and
(4R)-terpinen-4-ol, using H2O2 in presence of V2O5 [3].
The tosylation of alcohols is a very common reaction, which is often used to
facilitate subsequent nucleophilic substitution. A number of alcohols have been
converted to the corresponding arenesulfonates by using lengthy the conventional
tosylation procedures, in which the tosylates have been prepared in pyridine [4].
The first step of our reaction required the preparation of the 2-tosyl derivative
(2a). We used two different approaches in order to optimize yields and simplify
reaction workup (Scheme 1).
First, the tosylation reaction was performed in the usual way using pyridine as
the base. However, it was observed that the formation of the pyridinium salts in this
kind of reaction resulted in a concomitant loss of the desired tosylate. Also, accord-
ing to the conventional tosylation, when the tosylate prepared is an oil (like in our
Scheme 1

A Novel Route to trans-Epoxidation of Terpinen-4-ol
37
case) a thorough elimination of the pyridine from the final product requires either
repeated neutralization with aqueous hydrochloric acid or purification by column
chromatography.
Many of the tosylations reported in literature [5] were carried out by using
chloroform as the solvent and in order to eliminate the disadvantages mentioned
above, we performed the tosylation reaction under these conditions. This procedure
avoids formation of unwanted pyridinium salts inherent to reactions where higher
relative quantities of pyridine are employed.
It has to be mentioned that freshly purified tosyl chloride [6] should be used for
best results, because upon prolonged standing the material develops impurities of
p-toluenesulfonic acid and HCl. This method is advantageous over the conven-
tional tosylation in pyridine, regarding the work-up procedure, the yield, and the
purity of the product.
The highest yields of pure tosylate based on starting alcohol were obtained
using a 1:2:3 ratio of alcohol=tosyl chloride=pyridine in chloroform. Our results
are summarized in Table 1.
The second step of the method requires the treatment of the obtained 2-tosyl
derivative with a methanolic solution of potassium hydroxide in order to prepare
(1S,2R,4S)-1,2-epoxy-p-menthan-4-ol (3a). This process is stereoselective and
takes place by an SN2 intramolecular substitution in quantitative yield.
In order to derive the structure of 3a, chemical reactions, which involve oxirane
opening were performed. Opening of cyclohexene oxides generally proceeds in
such fashion that the trans-diaxial rather than the trans-diequatorial product is
obtained (F€urst-Plattner rule [7, 8]).
In the case of the cis-epoxide of terpinen-4-ol [9], axial attack at the higher
substituted C1 by water (SN2) upon the protonated epoxide leads to 1a where the
two hydroxyl groups have trans-diaxial orientation. The same compound was
obtained when the trans-epoxide of terpinen-4-ol reacted with water (Scheme 2).
Table 1. Tosylation of 1a in chloroform
Entry
Alcohol=mmol
p-TsCl=mmol
Pyridine=mmol
Yield=%
1
2
3
4
10
10
10
10
10
10
20
20
10
20
30
60
58
62
70
65
Scheme 2

38
E. Kozma et al.
Scheme 3
For a better explanation of the different behavior of the two epoxides, the
reaction of the trans-epoxide in a sodium acetate buffered solution of acetic acid
was investigated.
Three major effects must be considered when a reaction involves cyclohexene
epoxides ring opening: conformational effects, the primary steric effect (the incom-
ing reagent in the attack of an epoxide normally attacks the least substituted carbon
of the oxirane linkage unless there are remarkable polar or conjugative effects), and
conformational preference of the resulting products.
In the case of nucleophilic attack, the primary steric effect is observed for the
cis-isomer, for which diaxial opening involves attack at the tertiary carbon. For the
trans-isomer we cannot rationalize the formation of 5a on the basis of any steric
effect, the formation of this secondary product can be explained by the existence of
a partial positive charge on the tertiary carbon atom, the reaction approaching an
SN1 mechanism.
The action of acetic acid–sodium acetate solution upon 3a (Scheme 4) at the
less substituted C(2) center leads to diaxially disubstituted chair conformation of
4a (major product) and an attack at more substituted C(1) center gives rise to the
diaxially disubstituted twist conformation of the cyclohexane ring which must then
invert to the diequatorially disubstituted chair form of 5a with trans-diequatorial
orientation of the acetoxy and hydroxyl groups (minor product). In the same man-
ner, 3b gave the other enantiomer 4b as major product.
Scheme 4

A Novel Route to trans-Epoxidation of Terpinen-4-ol
39
In summary, it is apparent that in reactions of nucleophilic reagents on cis- and
trans-epoxides of terpinen-4-ol, the F€urst-Plattner rule of diaxial opening correctly
predicts the predominant products.
Experimental
(1S,2S,4S)-2-Tosyl-p-menthane-1,4-diol (2a, C17H28SO5)
(1S,2S,4S)-p-Menthane-1,2,4-triol (1a, 1.88g, 10mmol) was dissolved in 10cm3 of CHCl3 at room
temperature. Pyridine (2.41 cm3, 30mmol) was then added, followed by 3.81 g of p-toluenesulfonyl
chloride (20 mmol) in small portions with constant stirring. The reaction was completed after 24h.
Ether (40 cm3) and 10 cm3 of H2O were added and the organic layer was washed successively with 2 N
HCl, 5% NaHCO3 solution, and H2O and then dried (MgSO4). The solvent was removed under
reduced pressure and the crude tosylate was chromatographed (ethylacetate:toluene ¼ 5:1) on a silica
gel column to yield 2.39g of an oil (70%); [ꢀ]D ¼ þ32ꢁ cm3 gꢂ1 dmꢂ1 (c ¼ 1.0 in EtOH). (1R,2R,4R)-
2-Tosyl-p-menthane-1,4-diol (2b), [ꢀ]D ¼ ꢂ28.9ꢁ cm3 gꢂ1 dmꢂ1 (c ¼ 1.0 in EtOH) was obtained in
pure form from (1R,2R,4R)-p-menthane-1,2,4-triol (1b). 1H NMR (DMSO-d6, 500 MHz): ꢁ ¼ 7.7
(1H, d, Carom), 7.55 (1H, d, Carom), 7.35 (1H, d, Carom), 7.1 (1H, d, Carom), 4.75 (1H, s, C4OH),
3.75 (1H, s, C1OH), 2.0 (1H, dd, H3eq), 1.8 (1H, dd, H6eq), 1.6 (1H, dd, H5eq), 1.40 (1H, hept., H8), 1.35
(1H, dd, H3ax), 1.24 (1H, dd, H6ax), 1.20 (1H, dd, H5ax), 1.3 (3H, s, CH3), 1.2 (3H, s, CH3), 0.9 (6H, d,
2CH3) ppm; 13C NMR (DMSO-d6, 125 MHz): ꢁ ¼ 144.2 (C14), 138.0 (C11), 128.5 (C13), 125.0 (C12),
75.5 (C2), 71.3 (C1), 69.4 (C4), 36 (C3), 34.0 (C8), 32.5 (C5), 30.8 (C6), 21.3 (C15), 21.0 (C7), 17.1 (C9
and C10) ppm; MS: m=z (%) ¼ 127 (47), 109 (49), 83 (50), 71 (49), 57 (95), 55 (61), 43 (100).
Synthesis of (1S,2R,4S)-1,2-Epoxy-p-menthan-4-ol (3a)
To a solution of potassium hydroxide (20 mmol) in 10 cm3 of methanol 3.42 g of (1S,2S,4S)-2-tosyl-
p-menthane-1,4-diol (2a) (10 mmol) were added and the reaction mixture was stirred at room
temperature for 24 h. After this time, the solution was poured into water and extracted with ether.
The extracts were washed with water and dried over anhydrous sodium sulfate. The solvent was
removed in vacuo and the product was chromatographed (ethylacetate:toluene ¼ 5:1) on a silica
gel column to yield 1.56 g of an oil (92%); [ꢀ]D ¼ þ3.5ꢁ cm3 gꢂ1 dmꢂ1 (c ¼ 0.2 in EtOH) (Ref. [2]
[ꢀ]D ¼ þ3.2ꢁ cm3 gꢂ1 dmꢂ1 (c ¼ 0.2 in EtOH)). (1R,2S,4R)-1,2-Epoxy-p-menthan-4-ol (3b), [ꢀ]D ¼
ꢂ3.4ꢁ cm3 gꢂ1 dmꢂ1 (c ¼ 1.0 in EtOH) was obtained in a similar way from (1R,2R,4R)-2-tosyl-p-
1
menthane-1,4-diol (2b). H-NMR (DMSO-d6, 500 MHz): ꢁ ¼ 4.0 (1H, s, C4OH), 2.8 (1H, t, H2),
1.92 (1H, dd, H3eq), 1.8 (1H, dd, H6eq), 1.65 (1H, dd, H5eq), 1.40 (1H, hept., H8), 1.35 (1H, dd,
H3ax), 1.24 (1H, dd, H6ax), 1.20 (1H, dd, H5ax), 1.1 (1H, s, CH3), 0.9 (6H, d, 2CH3) ppm; 13C-NMR
(DMSO-d6, 125 MHz): ꢁ ¼ 70.0 (C4), 59.0 (C2), 57.0 (C1), 34.5 (C3), 32.8 (C8), 29.5 (C5), 26.3 (C6), 23
(C7), 16.2 (C9), 16.1 (C10) ppm; MS: m=z (%) ¼ 170 (4), 109 (32), 71 (28), 55 (39), 43 (100).
Synthesis of (1S,2S,4S)-2-Acetoxy-p-menthan-1,4-diol (4a)
(1S,2R,4S)-1,2-Epoxy-p-menthan-4-ol (0.5g, 3 mmol) was added to a solution of 1.5g of sodium
acetate in 10cm3 of glacial acetic acid and stirred at room temperature for 48h. After this period,
the solution was diluted with 300 cm3 of H2O, neutralized with sodium bicarbonate, and extracted with
chloroform and dried over anhydrous sodium sulfate. The chloroform was evaporated and the crude
product was chromatographed. Ethylacetate eluted (1S,2S,4S)-2-acetoxy-p-menthan-1,4-diol as an oil
which gave 0.58 g of needles from ether (82%); mp 115ꢁC; [ꢀ]D ¼ þ27.2ꢁ cm3 gꢂ1 dmꢂ1 (c ¼ 1.1 in
EtOH) (Ref. [10] [ꢀ]D ¼ þ27.8ꢁ cm3 gꢂ1 dmꢂ1; c ¼ 1.15 in EtOH). Further elution gave (1S,2R,4S)-p-
menthane-1-acetoxy-2,4-diol (5a) as an oil which gave crystals from ether. (1R,2R,4R)-p-Menthane-2-

40
E. Kozma et al.: A Novel Route to trans-Epoxidation of Terpinen-4-ol
acetoxy-1,4-diol (4b), [ꢀ]D ¼ ꢂ25.8ꢁ cm3 gꢂ1 dmꢂ1 (c ¼ 1.0 in EtOH) was obtained in the same way
from (1R,2S,4R)-1,2-epoxy-p-menthan-4-ol. 1H-NMR (DMSO-d6, 500 MHz): ꢁ ¼ 4.65 (1H, s, C4OH),
3.7 (1H, s, C1OH), 3.4 (1H, dd, H2), 1.98 (3H, s, COCH3), 1.90 (1H, dd, H3eq), 1.8 (1H, dd, H6eq), 1.65
(1H, dd, H5eq), 1.40 (1H, hept., H8), 1.30 (1H, dd, H3ax), 1.24 (1H, dd, H6ax), 1.20 (1H, dd, H5ax), 1.1
(3H, s, CH3), 0.83 (6H, d, 2CH3) ppm; 13C-NMR (DMSO-d6, 125MHz): ꢁ ¼ 169.5 (C11), 75.0 (C2),
71.1 (C1), 69.2 (C4), 35.8 (C3), 34.0 (C8), 32.5 (C5), 30.7 (C6), 23.8 (C12), 21.2 (7), 17.0 (C9 and C10)
ppm; MS: m=z (%) ¼ 127 (75), 109 (82), 99 (34), 81 (46), 71 (59), 55 (37), 43 (100).
Acknowledgements
E. Kozma acknowledges a short term fellowship in the CEEPUS SK-20 network and thanks the
€
Bundesministerium fur Bildung, Wissenschaft und Kultur (BMBWK), Austria, for an Ernst Mach
fellowship.
References
[1] Ohloff G, Uhde G (1965) Helv Chim Acta 48: 11
[2] Garside P, Halsall TG, Hornby GM (1969) J Chem Soc C: 716
[3] Cristea I, Kozma E, Batiu C (2002) Tetrahedron Asym 13: 915
[4] Marvel CS, Sekera VC (1955) Org Synth Coll 3: 366
[5] Kabalka GW, Varma M, Varma RS (1986) J Org Chem 51: 2386
[6] Pelletier SW (1953) Chem Ind (London) 1064
€
[7] Furst A, Plattner PA (1951) Abstracts. 12th International Congress of Pure and Applied
Chemistry, New York, p 409
[8] Royals EE, Leffingwell JC (1966) J Org Chem 31: 1937
[9] Frank WC (1998) Tetrahedron Asym 9: 3745
[10] Pailer M, Scheidl O, Gutwillinger H, Klein E, Obermann H (1981) Monatsh Chem 112: 987