Synthesis of novel acetates of β -caryophyllene under solvent-free lewis acid catalysis

Article abstract of DOI:10.1080/14786410903031500

Acylation of β-caryophyllene, a sesquiterpene hydrocarbon with acetic anhydride, was carried out under mild catalytic conditions using Lewis acids such as BF₃ Et₂O, ZnCl₂, FeCl₃, I₂ and AlCl₃

Full text of DOI:10.1080/14786410903031500

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Natural Product Research: Formerly
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Synthesis of novel acetates of β-
caryophyllene under solvent-free Lewis
acid catalysis
Bandna a , Vikas Jaitak a , V.K. Kaul a & Bikram Singh a
a Natural Plant Products Division, Institute of Himalayan
Bioresource Technology (CSIR), Palampur 176061, Himachal
Pradesh, India
Published online: 22 Sep 2010.
To cite this article: Bandna , Vikas Jaitak , V.K. Kaul & Bikram Singh (2009) Synthesis of novel
acetates of β-caryophyllene under solvent-free Lewis acid catalysis, Natural Product Research:
Formerly Natural Product Letters, 23:15, 1445-1450, DOI: 10.1080/14786410903031500
To link to this article: http://dx.doi.org/10.1080/14786410903031500
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Natural Product Research
Vol. 23, No. 15, 15 October 2009, 1445–1450
Synthesis of novel acetates of b-caryophyllene under solvent-free Lewis
acid catalysis
*
Bandna, Vikas Jaitak, V.K. Kaul and Bikram Singh
Natural Plant Products Division, Institute of Himalayan Bioresource Technology (CSIR),
Palampur 176061, Himachal Pradesh, India
(Received 13 February 2009; final version received 7 May 2009)
Acylation of ꢀ-caryophyllene, a sesquiterpene hydrocarbon with acetic anhydride,
was carried out under mild catalytic conditions using Lewis acids such as
BF3 Á Et2O, ZnCl2, FeCl3, I2 and AlCl3 as catalysts. Among these, BF3 Á Et2O was
found to catalyse the reaction most efficiently, yielding three acylated products in
75% yield under solvent-free conditions. The structures were confirmed by NMR
and MS techniques.
Keywords: ꢀ-caryophyllene; sesquiterpene hydrocarbon; acylation;
Lewis acids
1. Introduction
Sesquiterpene hydrocarbons are a class of high boiling volatile constituents and some of
these are used in fragrances because of their pleasant odour. Among these, ꢀ-caryo-
phyllene is a sesquiterpene hydrocarbon present in many essential oils, e.g. clove,
cinnamon and copaiba balsam oil, which are used as natural essential oils in many
fragrances. Use of ꢀ-caryophyllene is reported to be at 33% among 300 analysed cosmetic
products in the Dutch market (De Groot, Weyland, & Nater, 1994). Its odour is described
as woody and balsamic (Verghese, 1994), and it has been a commonly used fragrance
material since 1930 (Opdyke, 1973). Chemical analyses of 71 deodorants in the European
market in 1998 (Rastogi et al., 1998) revealed that 45% of the analysed products contained
ꢀ-caryophyllene as one of the ingredients (Skold, Karlberg, Matura, & Borje, 2006). As
with sesquiterpenes, the use of ꢀ-caryophyllene is very limited in perfumery; however, its
acetates are rated as high-valued odour constituents. Different methods of acylation of
many sesquiterpene hydrocarbons, including ꢀ-caryophyllene, have been reported
(Daeniker, Hochstetler, Kaiser, & Kitchens, 1972; Panten, Bertram, & Surburg, 2004)
with acetyl chloride or acetic anhydride, in the presence of an acid catalyst. This study was
carried out to synthesise novel acetates of ꢀ-caryophyllene by acylation with acetic
anhydride in the presence of BF3 Á etherate without the use of solvents. Acylation of
ꢀ-caryophyllene is a significant transformation, since it affords value-added products that
are used in perfumery as odour-modifying agents.
*Corresponding author. Email: vkaul2002@yahoo.co.in
ISSN 1478–6419 print/ISSN 1029–2349 online
ß 2009 Taylor & Francis
DOI: 10.1080/14786410903031500
http://www.informaworld.com

1446
Bandna et al.
Table 1. Effect of various solvents on the yield of acylated products of ꢀ-caryophyllene
under Lewis acid conditions.
Yield (%)
Entry
Lewis acid
Solvent
Time (h)
I
II
III
Total yield (%)
1
2
3
4
5
6
7
8
9
BF3 Á Et2O
BF3 Á Et2O
BF3 Á Et2O
BF3 Á Et2O
BF3 Á Et2O
BF3 Á Et2O
BF3 Á Et2O
ZnCl2
CH2Cl2
THF
MeCN
MeOH
EtOH
i-PrOH
0
–
–
–
–
0
5
15
5
20
18
25
10
15
20
–
8
5
15
5
20
18
75
30
43
51
–
1
1
1
1
1
1
1
1
1
1
–
–
–
–
–
10
5
8
6
–
–
–
–
–
–
–
40
15
20
25
–
FeCl3
I2
AlCl3
10
11
H
H
H
H
Ac2O, BF3 . etherate
r.t.,1 hr
OH
OCOCH3
H
H
H
H
H
OCOCH3
COCH3
COCH3
I (10% )
b-Caryophyllene
II (40%)
III (25%)
Scheme 1. Lewis acid catalysed acylation of ꢀ-caryophyllene.
2. Results and discussion
In this study, acylation of ꢀ-caryophyllene was carried out with different Lewis acids
(AlCl3, ZnCl2, FeCl3, I2 and BF3 Á etherate), and yields of acylated derivatives were
compared (Table 1, Entries 7–10). Reaction with acetic anhydride and BF3 Á etherate
yielded three derivatives: (E)-3(6-hydroxy-6,10,10-trimethylbicyclo[7.2.0]undecan-2-ylide-
ne)butan-2-one (I), 5-acetyl-2,6,10,10-tetramethylbicyclo[7.2.0]undecan-2-yl acetate (II)
and 4,4,8-trimethyltricyclo [6.3.1.02,5]dodecanyl acetate (III).
Previously, acylation of ꢀ-caryophyllene has been reported with acetic anhydride in the
presence of acid catalysts, including protic acids such as phosphoric acid or p-toluene–
sulphonic acid, and in the presence of Lewis acids such as BF3, AlCl3, SnCl4 and ZnCl2.
These reactions have been carried out at high temperatures (between 60 and 80ꢀC) with
reaction times between 2 and 7 h, and the two acylated products, i.e. 5-acetyl-2,6-
dimethylene-10,10-dimethylbicyclo[7.2.0]undecanene and 1-acetyl-11-methylene-4,7,7-tri-
methyl-cycloundeca-4,8-diene, were formed with 60–70% combined yield (Heinrich et al.,
1976). Acylation of ꢀ-caryophyllene with aluminosilicate catalysts has also been reported
to yield ꢀ-caryophyllene acetate in 23% (Volcho et al., 2001). In this study, BF3 Á etherate
catalysed acylation of ꢀ-caryophyllene in the presence of acetic anhydride without the
use of solvents (Scheme 1) and this has novelty in terms of its yield conversion of 75% of
the three acylated derivatives, fixing the reaction time period for 1 h at 25ꢀC

Natural Product Research
Table 2. GC–MS analysis of products I, II and III.
1447
Entry
I m/z (%)
II m/z (%)
III m/z (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
278 (10)
246 (90)
231 (80)
203 (30)
190 (20)
175 (30)
163 (40)
147 (100)
135 (80)
119 (40)
105 (70)
91 (80)
308 (5)
246 (20)
231 (10)
203 (100)
188 (10)
175 (18)
161 (60)
147 (40)
133 (20)
119 (20)
105 (25)
95 (20)
81 (12)
69 (10)
55 (12)
–
264 (15)
204 (30)
189 (60)
175 (20)
161 (100)
148 (50)
133 (40)
121 (70)
111 (70)
93 (52)
81 (52)
69 (58)
55 (70)
53 (15)
–
79 (50)
69 (60)
55 (50)
51 (10)
–
room temperature. Of the three acetyl derivatives, two acetates, namely (E)-3(6-hydroxy-
6,10,10-trimethylbicyclo[7.2.0]undecan-2-ylidene)butan-2-one (I) and 5-acetyl-2,6,10,10-
tetramethylbicyclo [7.2.0]undecan-2-yl acetate (II), are reported for the first time, and
derivative III is a known ꢀ-caryophyllene acetate. The structures of acylated derivatives
were confirmed by GC–MS (Table 2) and NMR spectroscopy (Table 3). The presence of
four methyl groups in I were confirmed by DEPT at 135ꢀ, ꢁC values were 21.8, 32.8, 28.2
and 29.8 at C-13, 14, 15 and 16 positions, respectively. The presence of one exocyclic
double bond at C-12 was confirmed by HMBC correlation of ꢁC 132.8 with exocyclic
proton ꢁH 1.90 (s, 1H). The presence of a ketonic group (–COCH3) was confirmed by
correlation of ꢁC 200.3 at C-17 with ꢁH 2.33 (s, 3H). In compound II, the presence of six
methyl groups was confirmed by DEPT at 135ꢀ, showing ꢁC values at 21.0, 30.1, 21.1, 30.1,
21.8 and 21.5 at C-11, 12, 13, 15, 16 and 18 positions, respectively. The ester group at C-14
position was confirmed by HMBC correlation of ꢁH 2.30 (m, 1H), with ꢁC of 55.7 and
170.6 at C-5 and C-14 positions, respectively. In derivative III, –OCOCH3 group was
confirmed by the appearance of ꢁC 170.3 at C-18, which showed correlation with ꢁH 2.18
(–CH3) of the ester moiety. HMQC of ꢁH 1.32 and 1.58 with ꢁC 47.3 and 88.2 at C-4 and
C-8 positions, respectively, confirmed the presence of bridgehead carbon in III and these
values showed HMBC correlation of ꢁH 1.32 and 1.58, with ꢁC 41.2 at C-16 position.
Further confirmation of the derivatives was studied by GC–MS (m/z) at 278, 308 and 264
for derivatives I, II and III, respectively.
When reaction was carried out in the presence of AlCl3 without solvent at room
temperature (25ꢀC) for 1 h, no product was formed. On extending the reaction time to 6 h,
a rearranged sesquiterpene hydrocarbon humulene was formed. Reactions with ZnCl2,
FeCl3 and I2 catalysts were studied in the absence of a solvent, and it was observed that the
yield of the three acylated products was very low (10, 40 and 25%) in comparison to the
three products formed with BF3 Á etherate (75%) without the use of solvents. Comparative
studies were made with respect to yields for carrying out the reactions with and without the
use of solvents. When a reaction was carried out in the presence of solvents EtOH, MeOH,
MeCN, i-PrOH and THF, the reaction did not favour the formation of derivatives I and II

1448
Bandna et al.
1
Table 3. 13C and H NMR spectra of compounds I, II and III.
I
II
III
Carbon
13C
1H
–
13C
1H
13C
1H
1
2
3
4
152.8
36.3
47.3
25.1
44.5
82.2
38.5
2.48 (m, 1H)
–
45.3
27.2
1.96 (m, 1H)
1.15 (m, 1H)
1.40 (m, 3H)
1.12 (m, 1H)
1.36 (m, 1H)
–
1.40 (m, 1H)
1.49 (m, 1H)
1.39 (m, 1H)
1.49 (m, 1H)
1.61 (m, 1H)
1.80 (m, 1H)
–
2.60 (m, 1H)
1.90 (m, 1H)
1.28 (m, 1H)
1.40 (m, 1H)
1.20 (m, 1H)
1.40 (m, 1H)
–
1.22 (m, 1H)
1.42 (m, 1H)
1.28 (m, 1H)
1.40 (m, 1H)
1.90 (m, 1H)
1.98 (m, 1H)
–
1.72 (dd, 1H)
2.20 (dd, 1H)
1.90 (s, 1H)
1.22 (s, 3H)
0.80 (s, 3H)
1.24 (s, 3H)
1.20 (s, 3H)
1.40 (m, 1H)
1.60 (m, 1H)
1.39 (m, 1H)
1.67 (m, 1H)
2.30 (m, 1H)
1.68 (m, 1H)
1.20 (m, 1H)
1.39 (m, 1H)
1.29 (m, 1H)
1.38 (m, 1H)
1.92 (m, 1H)
–
41.8
25.7
5
47.0
47.3
37.1
55.7
29.6
36.4
6
7
79.1
47.1
18.2
36.8
8
9
24.2
30.4
31.7
49.9
32.6
37.1
88.2
42.3
40.1
2.78 (m, 1H)
1.88 (dd, 1H)
2.08 (dd, 1H)
–
10
11
33.1
34.2
1.78 (dd, 1H)
1.95 (dd, 1H)
1.24 (s, 3H)
21.0
34.2
12
13
14
15
16
17
18
19
132.8
21.8
32.8
28.2
29.8
200.3
30.1
21.1
170.6
30.1
21.8
0.85 (s, 3H)
1.20 (d, 3H)
–
1.99 (s, 3H)
1.58 (s, 3H)
–
21.8
31.8
29.2
22.4
41.2
1.24 (s, 3H)
0.83 (s, 3H)
1.20 (s, 3H)
2.18 (s, 3H)
1.32 (d, 1H)
1.58 (d, 1H)
–
212.2
21.5
2.02 (s, 3H)
170.3
but favoured a limited quantity of derivative III: 5–20% (Table 1, Entries 2–6).
With BF3 Á Et2O catalysis in the presence of dichloromethane, 58% yield of three products
was obtained, which is low in comparison to the reaction carried out with BF3 Á Et2O in the
absence of a solvent. The low percentage yield of I, II and III in the presence of solvents
might be due to the formation of some rearranged products.
Acylation with BF3 Á Et2O improved the odour of ꢀ-caryophyllene under solvent-free
conditions, in 1 h yielding three products that were separated and evaluated for their odour
perception.
3. Experimental
3.1. General experimental procedures
1H, 13C, DEPT, HMQC and HMBC were recorded in CDCl3 on a Bruker DRX-300
instrument using TMS as the internal standard; chemical shifts are reported in ꢁ (ppm)
relative to the TMS signal and coupling constants (J) in hertz. GC–MS analysis was
recorded on a GC–MS (QP2010) Shimadzu gas chromatograph-mass spectrometer fitted
with a BP-20 capillary column (length 30 Â 0.25 mm i.d with 0.25 mm film thickness).
Helium was used as the carrier gas, with a flow rate of 1.1 mL minÀ1 in split mode (1 : 50).
The temperature was programmed from 70–220ꢀC at 4ꢀC minÀ1, with a 4 min hold at 70ꢀC

Natural Product Research
1449
and a 5 min hold at 220ꢀC. Injector and interface temperatures were fixed at 250ꢀC and the
ion source temperature was set at 200ꢀC. Two microlitres of the sample was injected.
Column chromatography was carried out on silica gel (60–120 mesh), and TLC was
performed on silica gel G (Merck). Other chemicals used were from E Merck India, and ꢀ-
caryophyllene was procured from M/S Nishant Aromas, Mumbai, India, and its purity
was checked by GC–MS. It was 82% pure and its purity was enriched to 97%.
.
3.2. Acylation of b-caryophyllene with BF3 Et2O
To ꢀ-caryophyllene (612 mg, 2.9 mmol), acetic anhydride (1.49 mL) and BF3 Á Et2O
(1.41 mmol) were added. The reaction mixture was stirred without heating for 1 h at
room temperature (25ꢀC) using a magnetic stirrer. The progress of the reaction was
monitored by TLC every 15 min. The reaction product was then neutralised using 10%
KOH solution. This mixture was again stirred at room temperature for 10 min and then
extracted with ether (3 Â 10 mL). The ether extract was washed with water, dried over
anhydrous Na2SO4, filtered and evaporated under reduced pressure at 50 Æ 5ꢀC. The
reaction mixture (595 mg) was subjected to column chromatography over silica gel (60–120
mesh) using a gradient elution of pentane/ether with increasing proportion of 5, 10, 20 and
30% ether (v/v) in pentane to give four fractions (i–iv). Fraction (i) was discarded.
Fraction (ii) (80 mg) was rechromatographed over silica gel using a gradient elution of 1–
10% ether (v/v) in pentane, yielding I (62 mg). Fraction (iii) (320 mg) was rechromato-
graphed on silica gel using a gradient elution of 5–20% ether (v/v) in pentane, yielding II
(280 mg). Fraction (iv) (175 mg) was rechromatographed on silica gel using a gradient
elution of 10–30% ether (v/v) in pentane, yielding III (155 mg).
3.3. Acylation of b-caryophyllene with Lewis acids ZnCl2, FeCl3 and I2
To ꢀ-caryophyllene (612 mg, 2.9 mmol) in acetic anhydride (1.49 mL), a Lewis acid, i.e.
ZnCl2, FeCl3, I2 or AlCl3 (1.41 mmol), was added, and four reactions were carried out
separately. The reaction mixture was stirred without heating for 1 h at room temperature
(25ꢀC) using a magnetic stirrer. The progress of the reaction was monitored on TLC. The
reaction product was then neutralised using 10% KOH solution. This mixture (595 mg)
was again stirred at room temperature for 10 min and then extracted with ether
(3 Â 10 mL). The ether extract was washed with water, dried over anhydrous Na2SO4
filtered and evaporated under reduced pressure at 50 Æ 5ꢀC. The reaction mixture was
subjected to column chromatography over silica gel (60–120 mesh) using a gradient elution
of pentane/ether with increasing proportion of 5, 10, 20 and 30% ether (v/v) in pentane,
yielding I, II and III. Their yields are given in Table 1 (Entries 7–10).
Acknowledgement
V. Jaitak is grateful to CSIR, India, for SRF fellowship. The authors thank Mrs Vijaylata Pathania
for GC–MS and Mr R.K. Tandon for NMR analyses.

1450
Bandna et al.
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