Superacid cyclization of certain aliphatic sesquiterpene derivatives in ionic liquids

Article abstract of DOI:10.1007/s10600-006-0175-6

Superacid cyclization was demonstrated for the first time to be successful in those ionic liquids with functional groups that are stable in the reaction medium using aliphatic sesquiterpene derivatives as examples.

Full text of DOI:10.1007/s10600-006-0175-6

Chemistry of Natural Compounds, Vol. 42, No. 4, 2006
SUPERACID CYCLIZATION OF CERTAIN ALIPHATIC
SESQUITERPENE DERIVATIVES IN IONIC LIQUIDS
M. Grin′ko, V. Kul′chitskii, N. Ungur, and P. F. Vlad
UDC 547.596/597
Superacid cyclization was demonstrated for the first time to be successful in those ionic liquids with
functional groups that are stable in the reaction medium using aliphatic sesquiterpene derivatives as
examples.
Key words: ionic liquids, superacids, cyclization, sesquiterpenoids.
Ionic liquids have recentlyfound use in organic synthesis thanks to several of their important properties such as a broad
temperature range at which reactions can be carried out, the simplicityofworking up reaction mixtures, nonvolatility, the ability
to be regenerated and used repeatedly, etc. [1-5].
Despite the use of the liquids as reaction media in many organic reactions, their application for carrying out
electrophilic cyclization of terpenoids has not been reported. It is well known that this reaction plays an important role in the
development of biomimetic synthetic methods for many cyclic terpenoids, among which are practically important compounds.
Existing information on biomimetic cyclization of regularly constructed terpenoids demonstrated convincingly that
the preferred reagents for it are superacids at low temperatures. The reaction is chemically and structurally selective and
stereospecific [6].
It seemed interesting to determine if superacid cyclization could be carried out in suitable ionic liquids and its
efficiency.
R
OAc
R
OAc
a
a
OH
1, 3
7, 9
2
8
1, 7: R = OH
3, 9: R = SO Ph
2
CO CH
2
3
CO R
CO CH
2
2
3
a, b
+
4
10
11, 12
11: R = CH
3
12: R = H
_
4
_
6
N
N
N
N
[bmim]BF =
4
BF
[bmim]PF =
PF
6
6
5
5
.
a. FSO3H (5 equiv), [bmim]BF4 , CH2Cl2, -45°C, 15 min; b. 10% KOH, EtOH, boiling for 2 h
Institute of Chemistry, Academy of Sciences of Moldova, ul. Akademicheskaya, 3, Kishinev, MD-2028, Republic of
Moldova, fax: 373 22 739 775, e-mail: vlad_p@mail.md. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 354-356,
July-August, 2006. Original article submitted July 4, 2006.
0009-3130/06/4204-0439 ©2006 Springer Science+Business Media, Inc.
439

TABLE 1. Cyclization of Aliphatic Sesquiterpenoids 1-4 by Fluorosulfonic Acid in Ionic Liquids 5 and 6
Product composition, %
cyclic product hydrocarbons polymers
Substrate mass,
mg (mmol)
CH2Cl2
Ionic liquid 5 or
Reaction
Reaction
Substrate
volume, mL 6 volume, mL temperature, °C time, min
1
1
1
2
3
3
4
4
70 (0.315)
72 (0.324)
65 (0.293)
88 (0.333)
64 (0.185)
22 (0.064)
44 (0.169)
46 (0.169)
1.4
1.5
1.3
1.8
1.3
0.4
0.9
0.9
0.70 (5)
0.72 (5)
0.65 (6)
0.88 (5)
0.64 (5)
0.20 (6)
0.44 (5)
0.46 (6)
-45
-45
0
15
5
36 (7)
33 (7)
19
15
69
29
0
45
52
31
39
11
27
9
5
0 (7)
-45
-45
0
15
30
5
32 (8)
89 (9)
73 (9)
0
-45
0
30
15
86 (10) and 5 (11)
41 (10) and 7 (11)
0
0
51
We investigated the reactions of several aliphatic sesquiterpene derivatives with fluorosulfonic acid in ionic liquids.
The substrates were E,E-farnesol (1), its acetate (2), E,E-farnesylphenylsulfone (3), and the methyl ester of E,E-farnesylic acid
(4). Theionicliquidswere(1-butyl-3-methylimidazolium)tetrafluoroborate [bmim]BF (5)and(1-butyl-3-methylimidazolium)
4
hexafluorophosphate [bmim]PF (6). Ionic liquid 5 was preferred because reactions can be carried out at from -45 to -50°C in
6
it. As mentioned above, superacid cyclization in ordinary solvents is carried out at from -70 to -80°C. Ionic liquid 6 solidifies
at 0°C. This would have a substantial effect on the product yields. Table 1 lists the results and reactions conditions. CH Cl
2
2
was used as a co-solvent because of the high viscosity of the ionic liquids.
The best results for reactions carried out in 5 were obtained for cyclization of 3 and 4. The yields of bicyclic 9 [7] and
10 [8] were 89 and 86%, respectively. For farnesol and its acetate, which contain functional groups that are sensitive to the
acids, the yields of bicyclic 7 and 8 [9] were relatively low (36 and 32%, respectively) because rather large quantities of
hydrocarbons were formed. Apparently the functional groups of both starting 1 and 2 and cyclization products 7 and 8 were
solvolyzed. For cyclization of 4, a small quantity (5%) of the ester of β-monocyclofarnesyl acid 11 and the product of full
cyclization 10 were formed. Esters 10 and 11 were separated by selective saponification of monocyclic ester 11 on boiling the
products in alcoholic KOH for 2 h. Acid 12 was separated by methylation with diazomethane. Ester 11 was identified by
comparison with an authentic sample prepared by the previously reported method [10].
If the cyclization was carried out in 6, the yield was high (89%) only for cyclization of 3. Cyclization of 4 formed a
mixture of 10 and 11 in yields of 41 and 7%, respectively. Compounds 1 and 2 reacted with fluorosulfonic acid in [bmim]PF
6
to give only hydrocarbons and polymeric products.
In all instances products were isolated pure by column chromatography over silica gel and were identified spectrally
and chromatographically by comparison with authentic samples.
Thus, we demonstrated for the first time that ionic liquids can be used successfully for superacid cyclization of terpene
esters and phenylsulfones, i.e., compounds containing functional groups that are stable in the acidic medium.
EXPERIMENTAL
13
Melting points were determined on a Boetius heating stage. PMR [and C NMR] spectra were recorded in CDCl
3
on a Bruker AC-80 (80 and 30 MHz, respectively) and Gemini 300 (300 and 75 MHz, respectively) spectrometers with TMS
internal standard. IR spectra were recorded in CCl on a Specord 74 spectrophotometer. Column chromatography used Merck
4
60 silica gel (70-230 mesh). TLC used Silufol UV-25 plates. Spots were developed by Ce(SO ) (0.1%) in H SO (2 N) with
4 2
2
4
subsequent heating at 80°C for 5 min.
Superacid Cyclization of Aliphatic Sesquiterpenoids in Ionic Liquids. General Method. Solutions of 1-4 in the
appropriate volume ofionic liquids 5 or 6 and CH Cl were cooled to the temperatures listed in Table 1, stirred, and treated with
2
2
the corresponding volume of fluorosulfonic acid (5 equiv) in CH Cl cooled tothe same temperature. The mixtures were stirred
2
2
for the times shown in Table 1, treated with Et N (0.75 equiv), and extracted with hexane (3 × 25 mL). The hexane extract was
3
washed successively with water, H SO solution (10%), water, saturated NaHCO solution, and water, dried over anhydrous
2
4
3
440

Na SO , and filtered. Solvent was removed in vacuo. The reaction products were chromatographed over SiO . Table 1 lists
2
4
2
the results.
-1
(±)-Drimenol (7) from 1. IR spectrum (ν, cm ): 3627, 3450, 1664, 1030, 834. PMR spectrum (δ, ppm): 0.80 (3H,
s), 0.86 (6H, s), 1.76 (3H, s), 2.20 (1H, br.s), 3.67 (2H, m), 5.38 (1H, m). Compound 7 was identified by comparison of the
spectral properties with those in the literature [11].
-1
(±)-Driman-8α,11-diol 11-Monoacetate (8) from 2. IR spectrum (ν, cm ): 3585, 3485, 1735, 1240, 1030. PMR
spectrum ( , ppm): 0.78 (3H, s), 0.83 (3H, s), 0.85 (3H, s), 1.17 (3H, s), 2.02 (3H, s), 3.44 (2H, m). Compound 8 was identified
by comparison of the spectral properties with those in the literature [11].
-1
(±)-Drimenylphenylsulfone (9) from 3. IR spectrum (ν, cm ): 1320, 1145. PMR spectrum (δ, ppm, J/Hz): 0.68 (3H,
s), 0.83 (3H, s), 0.86 (3H, s), 1.70 (3H, s), 2.63 (1H, br.s), 3.12 (2H, d, J = 5), 5.48 (1H, br.s), 7.52-7.93 (5H, m). Compound
9 was identified by comparison of the spectral properties with those in the literature [7].
-1
Methyl Ester of (±)-Drim-7-en-11-oic Acid (10) from 4. IR spectrum (ν, cm ): 1730, 1640, 1380, 1362, 860. PMR
spectrum (δ, ppm): 0.90 (6H, s), 0.95 (3H, s), 1.58 (3H, s), 2.88 (1H, br.s), 3.63 (3H, s), 5.46 (1H, m). Compound 10 was
identified by comparison of the spectral properties with those in the literature [8].
-1
(±)-β-Monocyclofarnesyl Acid (12) from 4. IR spectrum (ν, cm ): 1244, 1423, 1635, 1685, 2866, 2927, 2958, 3411,
3469. PMR spectrum (300 MHz, δ, ppm, J/Hz): 1.00 (6H, s), 1.39-1.45 (2H, m), 1.52-1.59 (2H, m), 1.61 (3H, s), 1.91 (2H, t,
13
J = 6), 2.1-2.19 (5H, m), 2.21 (3H, d, J = 1.2), 5.73 (1H, d, J = 1.2). C NMR spectrum (75 MHz,δ, ppm): 19.39, 19.60, 19.96,
27.14, 28.71, 32.91, 35.18, 39.90, 41.91, 114.69, 128.17, 136.17, 164.02, 172.38.
-1
Methyl Ester of (±)-β-Monocyclofarnesyl Acid (11) from 12. IR spectrum (ν, cm ): 1028, 1070, 1147, 1221, 1358,
1383, 1435, 1647, 1720, 2866, 2935. PMR spectrum (300 MHz, δ, ppm, J/Hz): 0.99 (6H, s), 1.39-1.41 (2H, m), 1.51-1.59 (2H,
13
m), 1.60 (3H, s), 1.91 (2H, t, J = 6), 2.1-2.19 (4H, m), 2.20 (3H, d, J = 1.2), 3.69 (3H, s), 5.70 (1H, d, J = 1.2). C NMR
spectrum (75 MHz,δ, ppm): 19.05, 19.59, 19.93, 27.17, 28.69, 32.89, 35.15, 39.89, 41.60, 50.95, 114.71, 128.04, 136.26,
161.18, 167.52.
ACKNOWLEDGMENT
We thank Prof. Aede de Groot (Agrarian University, Wageningen, Holland) for supplying a sample of [bmim]BF and
4
Prof. E. P. Serebryakov (IOC, RAS, Moscow) for supplying a sample of [bmim]PF .
6
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