Aluminum phenoxide-promoted alkylation of phenol with α- And β-pinenes

Article abstract of DOI:10.1007/s11172-013-0062-9

Alkylation of phenol with natural α- and β-pinenes in the presence of Al(OPh)₃ gives the O- and C-alkylation products with the structurally different terpene fragments. The terpenophenols obtained have proved to be optically active.

Full text of DOI:10.1007/s11172-013-0062-9

Russian Chemical Bulletin, International Edition, Vol. 62, No. 2, pp. 450—453, February, 2013
450
Aluminum phenoxideꢀpromoted alkylation of phenol with ꢀ and ꢀpinenes*
A. V. Kutchin, O. A. Shumova, and I. Yu. Chukicheva
Institute of Chemistry, Komi Scientific Center of the Ural Branch of the Russian Academy of Sciences,
48 ul. Pervomaiskaya, 167982 Syktyvkar, Russian Federation.
Fax: +7 (821) 221 8477. Eꢀmail: chukichevaꢀiy@chemi.komisc.ru
Alkylation of phenol with natural ꢀ and ꢀpinenes in the presence of Al(OPh)3 gives the
Oꢀ and Cꢀalkylation products with the structurally different terpene fragments. The terpenoꢀ
phenols obtained have proved to be optically active.
Key words: phenol, ꢀpinene, ꢀpinene, alkylation, aluminum phenoxide, terpenophenols.
Terpenophenols which are characterized by the strucꢀ
tural variety and a wide range of biological activity take
a special place among the natural products of the mixed
biogenesis.1 One of the methods for the preparation of
analogs of such natural compounds is a catalytic alkylaꢀ
tion of phenols with terpenoids.2—6 A significant contriꢀ
bution into the studies of alkylation of phenols with bicyꢀ
clic terpenes was made by L. A. Kheifits with coꢀworkers.7
In particular, they studied the alkylation of phenol with
ꢀpinene (the ratio of reactants 2 : 1) in the presence of
Al(OPh)3 and BF3•Et2O at 70 and 100 C.8,9 However,
enantiomeric composition of the reaction products was
not considered in these works.
In the present work, we studied in details specific feaꢀ
tures of alkylation of phenol 1 with (+)ꢀꢀpinene 2 and
(–)ꢀꢀpinene 3 in the presence of Al(OPh)3. The ratio of
the starting components and the temperature of the reacꢀ
tion were found to affect the composition and yield of
the optically active terpenophenols.
40—55% total yield of ethers 6 and 7. Besides, the use of
the equimolar amounts of the starting reactants afforded
the significant amount (35%) of oꢀisobornylphenol 4b,
whereas an excess of phenol facilitated the formation of
phenyl bornyl ether 5c. Heating of the reaction mixture at
160 C raised the total yield of ethers 6 and 7 to 74—77%
(Scheme 1, Table 1). The alkylation products were isolatꢀ
ed by column chromatography on silica gel.
The obtained compounds 4c and 5c have proved to be
optically active. 2ꢀBornylphenol 4c was found to be
enantiomerically enriched (data from HPLC on a chiral
column and NMR spectroscopy with the use of a chiral
shifting agent). The formation of compounds 4a,b and
5b,d was accompanied by the intramolecular rearrangeꢀ
ments of the terpene fragment, which led to their raceꢀ
mization.
The alkylation of phenol 1 with ꢀpinene 2 having an
endocyclic double bond required heating to 160 C. Carꢀ
rying out the reaction at 100 C irrespective of the ratio of
reactants led to alkylation products only in the trace
amounts (see Table 1).
The use of a twofold excess of ꢀpinene for the reꢀ
action at 160 C allowed us to obtain optically active
2ꢀbornylphenol 4c (34%) and phenyl bornyl ether 5c (49%)
(see Scheme 1, Table 1).
The equimolar ratio of the starting reactants resulted
in the predominant formation of the Oꢀalkylation prodꢀ
ucts: ethers with the isobornyl (5b) and bornyl (5c) strucꢀ
tures of the terpene fragment, as well as ethers of the chroꢀ
mane type 6 and 7 in 28% total yield, whereas the
Cꢀalkylation products 4b and 4e were obtained in 18 and
16% yields, respectively. The alkylation of phenol with
ꢀpinene under similar conditions led to ethers 6 and 7 in
up to 80% total yield. The use of an excess of phenol in the
case of ꢀpinene raised the yield of ethers of the chromane
type 6 and 7, however, the selectivity of the reaction genꢀ
erally was lower. These conditions (at 160 C) gave also
the phenol with the pꢀmenthene substituent 4e.
Earlier,6 we have shown that alkylation of phenol 1
with an excess of (–)ꢀꢀpinene 3 at both 100 C and 160 C
gave optically active compounds with the bornyl structure
of the terpene substituent: oꢀbornylphenol 4c (22 and 48%)
and phenyl bornyl ether 5c (46 and 35%), as well as ethers
of the chromane type 6 and 7 (32%) (Scheme 1). In the
present work, we found that the reaction between phenol 1
(1 or 2 equiv.) and ꢀpinene (1 equiv.) at 100 C gave the
* Dedicated to Academician of the Russian Academy of Sciences
S. M. Aldoshin on the occasion of his 60th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0451—0454, February, 2013.
1066ꢀ5285/13/6202ꢀ0450 © 2013 Springer Science+Business Media, Inc.

Terpenylphenols
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 2, February, 2013
451
Scheme 1
Reagents and conditions: i. ꢀpinene, 160 C, 6 h; ii. ꢀpinene, 100 or 160 C, 6 h.
In both cases, the formation of compound 4e is quite
explainable, since the opening of the strained fourꢀmemꢀ
bered ring of ꢀpinene occurred in acidic phenol medium
already at 100 C. In the excess of phenol, the formation of
the carbocation from ꢀpinene was determined by the proꢀ
tonꢀdonor properties of phenol, and the catalytic effect
of Al(OPh)3 on the alkylation process was lowered.
For the confirmation of the effect of acidic properꢀ
ties of phenol on the formation of carbocation from
ꢀpinene, we studied in this work the alkylation of Al(OPh)3
with ꢀpinene at 100 and 160 C. The analysis of the alkyꢀ
lation products showed that the reaction took place in the
organized sphere of aluminum phenoxide (Scheme 2).
It should be noted that the reaction of Al(OPh)3 with
ꢀpinene proceeded with the complete conversion already
at 100 C. The major reaction product was optically active
phenyl bornyl ether 5c. Besides, a mixture of ethers with isoꢀ
bornyl (5b) and fenchyl (5d) substituents and ethers of the
chromane type 6 and 7 were formed (see Scheme 2, Table 2).
oꢀTerpenophenols with the bornyl (4c), isobornyl (4b),
and pꢀmenthenyl (4e) structures of the terpene fragment
were also among the products. Since phenol did not present in
the free form in the reaction mixture, the formation of the
carbocation from ꢀpinene took place in the sphere of alumꢀ
inum phenoxide, which was an electron pair acceptor.7,10
The increase in the temperature to 160 C led to the
opening of the strained fourꢀmembered ring of ꢀpinene
with the predominant formation of ethers 6 and 7 (57%
total yield), as well as orthoꢀsubstituted phenols 4a—c.
These results differ from the data represented above on the
alkylation of phenol with ꢀpinene involving catalytic
amounts of Al(OPh)3.
Scheme 2
Al(OPh)3 + 2
4a + 4b + 4c + 4e + 5b + 5c +
+ 5d + 5e + 6 + 7
Table 1. Alkylation products of phenol with ꢀ and ꢀpinenes
Ratio
Composition of the reaction products (%)
1 : pinene
4а
4b
4c
4е
5a
5b
5c
6
7
ꢀPinene 2, 160 С
1 : 1
1 : 2
2 : 1
—
—
1
18
—
15
—
34
15
16
—
17
1
2
1
10
12
13
24
49
11
19
19
29
19
14
28
ꢀPinene 3, 100 С (160 С)
1 : 1
1 : 2
2 : 1
9
(–)
—
(2)
—
35
(14)
—
—
(9)
22
(48)
3
—
—
—
—
—
—
16
—
21
(60)
23
(6)
35
19
(17)
19
(2)
20
—
46
(35)
32
—
—
(–)
(–)
(4)
(40)
(34)

452
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 2, February, 2013
Kutchin et al.
20
Table 2. Composition of the alkylation products of
aluminum phenoxide with ꢀpinene 2 at 100 and
160 C*
[]D +44 (neat), (1S)ꢀ(–)ꢀꢀpinene purchased from Alfa Aeꢀ
20
sar (99% purity), []D –21 (neat). Aluminum phenoxide
Al(OPh)3 was used as the catalyst, which was synthesized in situ.
Phenol was commercially available from Alfa Aesar and was
used without additional purification.
Product
Content (%)
160 С
Alkylation of phenol with ꢀpinene in the presence of Al(OPh)3
(general procedure). Aluminum flakes (0.017 g, 0.21 mmol) were
added in small portion to phenol 1 (2 g, 21 mmol) preheated to
160 C. After the reaction of aluminum with phenol was comꢀ
pleted, the mixture was cooled to 40 C, followed by the addition
of ꢀpinene 2 (1, 2, or 0.5 equiv.). The reaction mixture was
heated for 6 h at 160 or 100 C and subjected to chromatography
on a column with SiO2.
The spectroscopic characteristics of the known isolated comꢀ
pounds 4a,b, 5a,b, 6, and 7 agree with the literature data.3,6,10
endoꢀ2ꢀ(2ꢀHydroxyphenyl)ꢀ1,7,7ꢀtrimethylbicyclo[2.2.1]ꢀ
heptane (4c). Partially crystalline yellow substance. Found (%):
C, 83.00; H, 9.56. C16H22O. Calculated (%): C, 83.43; H, 9.63.
[]D23 –42.7 (c 0.4; CHCl3). HPLC: er 78.5%. 1H NMR, : 0.83
(s, 3 H, C(10)H3); 0.99 (s, 3 H, C(8)H3); 1.13 (s, 3 H, C(9)H3);
1.52—1.66 (m, 2 H, H(5), H(6)); 1.81—1.84 (m, 2 H, H(3),
H(6)); 1.84—1.92 (m, 2 H, H(4), H(5)); 2.18—2.26 (m, 1 H,
H(3)); 3.55 (ddd, 1 H, H(2), J = 3.1 Hz, J = 5.6 Hz, J = 11.8 Hz);
4.72 (s, 1 H, OH); 6.81 (m, 1 H, H(13)); 6.99 (m, 1 H, H(15));
7.10 (m, 1 H, H(14)); 7.30 (d, 1 H, H(16), J = 7.0 Hz). 13C NMR,
: 15.07 (C(10)), 18.72 (C(9)), 19.85 (C(8)), 28.31 (C(5)), 28.92
(C(3)), 35.18 (C(6)), 41.90 (C(4)), 45.58 (C(2)), 50.39 (C(1)),
50.56 (C(7)), 115.02 (C(13)), 119.00 (C(15)), 125.38 (C(16)),
127.94 (C(11)), 130.02 (C(14)), 154.70 (C(12)).
100 С
4а
4b
4c
4е
5b
5c
5d
5е
6
—
5
25
5
3
53
3
—
3
3
10
14
6
—
—
9
4
1
36
20
7
* The ratio Al(OPh)3 : 2 = 1 : 1, the reaction time 6 h,
the 100% conversion.
In conclusion, when Al(OPh)3 is used as the catalyst,
the selectivity of the alkylation of phenol with ꢀ or
ꢀpinene depends on the reaction temperature and the
ratio of the starting reactants. Besides the catalytic effect
of Al(OPh)3, the composition of the alkylation products is
affected by the structure of the carbocation formed from
the starting pinene.
2ꢀ(1ꢀIsopropylꢀ4ꢀmethylcyclohexꢀ3ꢀenyl)phenol (4e). Dense
oily light brown liquid. Found (%): C, 83.15; H, 9.52. C16H22O.
Calculated (%): C, 83.43; H, 9.63. []D –3.1 (c 0.9; CHCl3).
23
Experimental
1H NMR, : 1.26 (d, 6 H, C(8)H3, C(9)H3, J = 3.0 Hz);
1.41—1.47 (m, 1 H, H(5)); 1.72 (s, 3 H, C(10)H3); 1.87—2.20
(m, 6 H, H(3), H(5), H(6), H(7)); 5.46 (m, 1 H, H(2)); 5.29
(s, 1 H, OH); 7.00 (d, 2 H, H(12), H(16), J = 9.0 Hz); 7.09
(m, 1 H, H(14)); 7.29 (m, 2 H, H(13), H(15)). 13C NMR,
: 23.38 (C(8), C(9)); 24.17 (C(5)); 24.51 (C(10)); 27.14 (C(3));
31.07 (C(6)); 43.93 (C(7)); 82.66 (C(4)); 120.73 (C(14)); 123.05
(C(2)); 124.16 (C(12), C(16)); 128.83 (C(13), C(15)); 134.11
(C(1)); 155.48 (C(11)).
endoꢀ1,7,7ꢀTrimethylꢀ2ꢀphenoxybicyclo[2.2.1]heptane (5c).
Colorless oily liquid. Found (%): C, 83.80; H, 9.86. C16H22O.
Calculated (%): C, 83.43; H, 9.63. []D23 +80.3 (c 1.05; CHCl3).
HPLC: er 77%. 1H NMR, : 0.96 (s, 3 H, C(10)H3); 0.97 (s, 3 H,
C(8)H3); 0.99 (s, 3 H, C(9)H3); 1.14—1.19 (m, 2 H, H(5), H(6));
1.28—1.42 (m, 2 H, H(3), H(6)); 1.78—1.80 (m, 2 H, H(4),
H(5)); 2.36—2.45 (m, 1 H, H(3)); 4.36 (br.d, 1 H, H(2), J = 9.0 Hz);
6.88—6.97 (m, 3 H, H(12), H(14), H(16)); 7.28—7.33 (m, 2 H,
H(13), H(15)). 13C NMR, : 13.77 (C(10)); 18.98 (C(9)); 19.76
(C(8)); 26.81 (C(5)); 27.98 (C(3)); 36.87 (C(6)); 45.21 (C(4));
45.22 (C(1)); 47.57 (C(7)); 82.73 (C(2)); 115.48 (C(12), C(16));
120.11 (C(14)); 129.35 (C(13), C(15)); 159.21 (C(11)).
1
H and 13C NMR spectra of the compounds obtained were
recorded on a Bruker Avance II 300 spectrometer (300.17 and
75.5 MHz, respectively) in CDCl3. The residual signals of chloroꢀ
form (H 7.26, C 76.90) were used as an internal reference. The
signals in the 13C NMR spectra were assigned using the JMOD
procedure. Specific rotation was measured on a Kruss Optronic
P3002RS automatic digital polarimeter. Optical purity of enanꢀ
tiomerically enriched terpenophenols was determined by HPLC on
an Agilent 1100 instrument (UV detector,  = 219 and 254 nm,
20 C), using a column with a Chiralcel ODꢀH chiral stationary
phase, eluent hexane—isopropyl alcohol (99 : 1), the eluent flow
rate 1 mL min–1
.
The monitoring of the terpenophenol purity and the analysis
of the volatile reaction products were performed by GLC on
a Shimadzu GCꢀ2010AF chromatograph using an HPꢀ1 capilꢀ
lary column (60 m × 0.25 mm × 0.25 m, the temperature mode
100—240 C at the rate of heating 6 deg min–1). Flameꢀionizing
detector was used, carrier gas was helium.
The reaction progress was monitored by TLC on Sorbfil
plates; the components were visualized by treatment of the plates
either with an alcoholic solution of vanillin with subsequent heatꢀ
ing to 100—150 C or a solution of KMnO4 (15 g of KMnO4,
300 mL of H2O, 0.5 mL of conc. H2SO4). The reaction products
were isolated by column chromatography on Alfa Aesar silica gel
70/230 (eluent light petroleum—Et2O with the increase of perꢀ
centage of the latter).
1,3,3ꢀTrimethylꢀ2ꢀphenoxybicyclo[2.2.1]heptane (5d). Colorꢀ
less oily liquid. Found (%): C, 83.67; H, 8.86. C16H22O. Calcuꢀ
lated (%): C, 83.43; H, 9.63. []D23 0 (c 0.2; CHCl3). 1H NMR,
: 0.93 (s, 3 H, C(8)H3); 1.03—1.09 (m, 2 H, H(5), H(7)); 1.17
(s, 3 H, C(10)H3); 1.24 (s, 3 H, C(9)H3); 1.31—1.34 (m, 1 H,
H(6)); 1.50—1.59 (m, 2 H, H(6), H(7)); 1.88 (m, 1 H, H(4));
2.09—2.13 (m, 1 H, H(5)); 3.93 (s, 1 H, H(2)); 6.95 (d, 2 H,
H(12), H(16), J = 9.0 Hz); 7.30 (m, 3 H, H(13), H(14), H(15)).
Bicyclic monoterpenes were used as the alkylating agents:
(+)ꢀꢀpinene purchased from Alfa Aesar (98% purity),

Terpenylphenols
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 2, February, 2013
453
13C NMR, : 19.96 (C(8)); 20.49 (C(10)); 25.93 (C(5)); 26.44
(C(6)); 30.57 (C(9)); 33.53 (C(3)); 41.47 (C(7)); 49.16 (C(4));
49.62 (C(1)); 90.11 (C(2)); 115.86 (C(12), C(16)); 120.08 (C(14));
129.32 (C(13), C(15)); 151.66 (C(11)).
3. V. V. Fomenko, D. V. Korchagina, N. F. Salakhutdinov,
V. A. Barkhash, Helv. Chim. Acta, 2002, 85, 2358.
4. H. Bienayme, J.ꢀE. Ancel, P. Meilland, J.ꢀP. Simonato,
Tetrahedron Lett., 2000, 41, 3339.
4ꢀIsopropylꢀ1ꢀmethylꢀ4ꢀphenoxycyclohexene (5e). Colorless
oily liquid. Found (%): C, 83.84; H, 8.90. C16H22O. Calculatꢀ
ed (%): C, 83.43; H, 9.63. 1H NMR, : 1.27 (d, 6 H, C(8)H3,
C(9)H3, J = 3.0 Hz); 1.44—1.48 (m, 1 H, H(5)); 1.73 (s, 3 H,
C(10)H3); 1.88—2.18 (m, 6 H, H(3), H(5), H(6), H(7)); 5.46
(m, 1 H, H(2)); 7.01 (m, 2 H, H(12), H(16)); 7.28 (m, 2 H,
H(13), H(14), H(15)). 13C NMR, : 23.39 (C(8), C(9)); 24.19
(C(6)); 24.52 (C(10)); 27.16 (C(5)); 31.09 (C(3)); 43.95 (C(7));
82.64 (C(4)); 120.75 (C(12), C(16)); 123.06 (C(2)); 124.17
(C(14)); 128.84 (C(13), C(15)); 134.09 (C(1)); 155.49 (C(11)).
5. I. Yu. Chukicheva, A. V. Kuchin, Ross. Khim. Zh., 2004,
48, No. 3, 21 [Mendeleev Chem. J. (Engl. Transl.), 2004,
48, No. 3].
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2012, 48, 43].
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dushistykh veshchestv i masel [Chemistry and Technology of
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Moscow, 1968, p. 142 (in Russian).
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44, 62].
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 12ꢀ03ꢀ00900ꢀa
and 12ꢀ03ꢀ31577 mol_a).
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Received January 21, 2013;
in revised form February 12, 2013