Camphor and isocamphanone in the synthesis of disubstituted acetylene alcohols, ethers, and esters

Article abstract of DOI:10.1023/A:1015549229781

By treating 1-octyne and phenylacetylene with butyllithium the corresponding lithium acetylides were obtained that, with camphor and isocamphanone, provided along streospecific process 2-exo-(1-octynyl or 2-phenyl-1-ethynyl)-2-endo-lithiumoxy-5,5,6-trimet

Full text of DOI:10.1023/A:1015549229781

Russian Journal of Organic Chemistry, Vol. 38, No. 2, 2002, pp. 182 187. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 2, 2002,
pp. 202 206.
Original Russian Text Copyright
2002 by Dikusar, Kozlov, Moiseichuk.
Camphor and Isocamphanone in the Synthesis
of Disubstituted Acetylene Alcohols, Ethers, and Esters
E. A. Dikusar, N. G. Kozlov, and K. L. Moiseichuk
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus’, Minsk, 220072 Belarus’
Received October 18, 2000
Abstract By treating 1-octyne and phenylacetylene with butyllithium the corresponding lithium acetylides
were obtained that, with camphor and isocamphanone, provided along streospecific process 2-exo-(1-octynyl or
2-phenyl-1-ethynyl)-2-endo-lithiumoxy-5,5,6-trimethylbicyclo[2.2.1]heptane and 2-endo-(1-octynyl or
2-phenyl-1-ethynyl)-2-exo-lithiumoxy-1,7,7-trimethylbicyclo[2.2.1]heptane. The hydrolysis of these lithium
alcoholates occurred selectively and resulted in individual tertiary terpene alcohols containing exo-acetylene
substituent in the case of camphor, endo-acetylene fragment in the case of isocamphanone. The alcohols
reacted with methyl, ethyl, or butyl iodides in the presence of hexamethylphosphoramide to afford ethers,
and with benzoyl chloride to furnish disubstituted esters of benzoic acid.
The interest to chemical transformations of terpene
compounds is due to the availability and chemical
lability of this compounds class. As a result, it is
possible to prepare therefrom the products of versatile
structures. Acetylene-containing terpene derivatives
do not exist in the nature and are not described in
the literature [1, 2]. However quite a number of
medicines is known to contain acetylene fragments,
in particular, substituted acetylene alcohols possess
a wide range of biological activity [3]. Therefore the
building into the structure of the natural biologically
active compounds a pharmacophoric acetylene moiety
providing new potentially bioactive substances is an
urgent problem.
lithiumoxy-1,7,7-trimethylbicyclo[2.2.1]heptane
(VIIIa, b) from lithium acetylides (IIa, b) prepared
by treating with butyllithium 1-octyne (Ia) or phenyl-
acetylene (Ib) reacted with camphor (IIIb) or iso-
camphanone (IIIa).
The alcoholates thus prepared IVa, b and VIIIa, b
were hydrolysed with water without separation from
the reaction mixture. The individual isomeric tertiary
terpene alcohols were isolated in 68 84% yield. The
acetylene fragment was in endo-position in alcohols
Va, b obtained from the isocamphanone, and in exo-
position in alcohols IXa, b from camphor.
The structure of compounds obtained was con-
firmed by IR and NMR spectra. In their IR spectra
are lacking the absorption bands of C=O group and
Csp H bond, and appear characteristic bands of the
The target of this study was a synthesis of a
multipurpose synthon that would permit preparation
of previously unknown individual isomeric disubstitut-
ed acetylene alcohols, ethers, and esters containing
in the structure a bicyclic terpene moiety from the
known drug, camphor [4], or its closest analog, iso-
camphanone.
1
stretching vibrations of the C C bond at 2220 cm
1
and of an associated hydroxy group at 3455 cm . In
the H NMR spectra of alcohols Va, b and IXa, b are
1
present proton signals both from the bicyclic moiety
and from the substituents in the side chain (Table 1),
and the pattern of the spectra is characteristic of
individual isomers evidencing the selectivity of the
We showed previously [5, 6] that as such synthons
could be used highly reactive lithium alcoholates of
various structures. They were brought into reaction
in statu nascendi, without isolation, and they were
able to undergo further transformation conserving the
initial configuration [7, 8]. In this study we carried
out for the first time a stereospecific synthesis of
2-exo-(1-octynyl or 2-phenyl-1-ethynyl)-2-endo-lith-
iumoxy-5,5,6-trimethylbicyclo[2.2.1]heptane (IVa, b)
and 2-endo-(1-octynyl or 2-phenyl-1-ethynyl)-2-exo-
1
reaction. However the H NMR spectra are not suf-
ficient for unambiguous location of the tertiary
hydroxy group.
The determination of the spatial arrangement of the
acetylene alcohols V, IX was carried out with the use
of 13C NMR spectra by comparison of the experi-
mental and calculated chemical shifts. The calcula-
tions were based on the chemical shifts of model
1070-4280/01/3802-182$27.00 2002 MAIK Nauka/Interperiodica

CAMPHOR AND ISOCAMPHANONE IN THE SYNTHESIS
183
I, II, IV, V, VII IX, XI, R = (CH2)5CH3 (a), Ph (b); V, IX, R = H; VI < X, R = (CH2)5CH3 (a c), Ph (d f);
R = CH3 (a, d), (CH2)3CH3 (c, f); VII, XI, R = COPh.
compounds, derivatives of [2.2.1]heptane [9 11]. The
chemical shift of C2 atom in the synthesized tertiary
alcohols is 80 ppm. The comparison of the spectra of
alcohols V, IX with those of borneol, isoborneol,
2-exo- and 2-endo-methylborneols [12], 2-methyl- and
2-phenylisoborneols [13] indicated that hydroxy
group at the C2 atom had endo-orientation in the case
of alcohols V obtained from isocamphanone, and exo-
orientation for alcohols IX prepared from camphor.
Therefore the acetylene fragment was located exo in
alcohols V and endo in alcohols IX. The configura-
tion of the substituents at the C2 atom is deduced
from the chemical shifts of C3, C6, and C8 10 atoms
that are sensitive to the change from endo to exo
orientation of the substituents due to the alteration of
the 1,4-through-space interaction [7, 8].
Lithium alcoholates IV, III with benzoyl chloride
afforded esters VIIa, b, XIa, b in 63 78% yield. In
the IR spectra of the esters the stretching vibrations
1
band of carbonyl group appears at 1730 cm . To the
phenyl groups in the IR spectra of these compounds
correspond three bands of stretching vibrations from
C H in the benzene ring at 3080, 3060, and
1
3030 cm , and bands of bending vibrations of the
1
benzene ring at 1600, 1580, 1500, 755, and 700 cm .
1
In the H NMR spectra of compounds VII, XI the
phenyl signals are present downfield at 7 8 ppm.
Compounds obtained are either colorless fluids
Va, VIa f”, VIIa, IXa, Xa f, XIa or crystalline
compounds Vb, VIIb, XIb well soluble in the
common organic solvents and insoluble in water.
Their 1H NMR spectra are presented in Table 1,
physical characteristics and yields in Table 2.
Lithium alcoholates IVa, b and VIIIa, b readily
react with methyl, ethyl, and butyl iodides in the
presence of hexamethylphosphoramide (HMPA) to af-
ford the corresponding ethers VIa f, Xa f) in 65
85% yield. Without HMPA the reaction does not
proceed. In the IR spectra of the ethers appears the
absorption band of stretching vibrations of the C O C
UV spectra of compounds obtained contain the
following absorption bands max, nm ( ): 204 2
(300 100) (Va, IXa, Xc); 204 3 (25000 2000),
241 1 (23000 3000), 252 1 (12000 2000)
(Vb, VId f, VIIb, IXb, Xd f); 204 1 (200 100),
235 5 (200 150) (VIa c, Xa, b); 203 (12000),
231 (24000) (XIa); 204 (30000), 237 (29000), 242
1
1
bonds at 1090 cm . The H NMR spectra of the
ethers unlike those of the initial compounds contain
the signal from OAlk groups at 3.5 ppm. Since it had
been shown before [7, 8] that configuration of the
substituents remained the same in the course of this
reaction, the endo-configuration was assigned to
ethers VI, and to ethers X exo-configuration.
(28000), 253 (22000)
(XIb).
EXPERIMENTAL
IR spectra were measured on IR Fourier spectro-
1
meter Protege-460 of Nicolet Co. H NMR spectra
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 2 2002

1
Table 1. H NMR spectra of compounds Va, b, VIa f, VIIa, b, IXa, b, Xa f, XIa, b
Compd. no.
, ppm
Va
Vb
0.80 1.05 m (12H, Me2C5, MeC6, MeCH2), 1.05 2.10 m [16H, OH, 3CH, CH2, (CH2)4], 2.18 (2H, CH2C C)
0.89 d (3H, MeC6, 3JH1 H 7.0 Hz), 0.92 s (3H, MeC5-endo), 1.09 s (3H, MeC5-exo), 1.55 2.10 m [7H, OH, 2CH, 2CH2], 2.16 br.s
(1H, HC1), 7.20 7.45 m (5H, Ph)
VIa
VIb
0.77 1.03 m (12H, Me2C5, MeC6, MeCH2), 1.03 2.02 m [15H, 3CH, 2CH2, (CH2)4], 2.21 t (2H, CH2C C, 3.26 s (3H, MeO)
0.77 1.03 m (12H, Me2C5, MeC6, MeCH2), 1.20 t (3H, MeCH2O), 1.20 2.03 m [15H, 3CH, 2CH2, (CH2)4], 2.21 t (2H, CH2C C),
3.17 3.80 m (2H, CH2O)
VIc
VId
0.77 1.03 m (15H, Me2C5, MeC6, 2MeCH2), 1.15 2.03 m [19H, 3CH, 2CH2, (CH2)2, (CH2)4], 2.22 t (2H, CH2C C), 3.15 3.70 m (2H, CH2O)
1
0.88 d (3H, MeC6, 3JH
7.0 Hz), 0.91 s (3H, MeC5-endo), 1.03 s (3H, MeC5-exo), 1.60 2.03 m [6H, 2CH, 2CH2], 2.16 br.s
H
(1H, HC1), 3.36 s (3H, MeO), 7.22 7.50 m (5H, Ph)
5
VIe
VIf
0.88 d (3H, MeC6, 3JH 1 7.0 Hz), 0.91 s (3H, MeC5-endo), 1.04 s (3H, MeC5-exo), 1.22 t (3H, MeCH2), 1.54 2.05 m [6H, 2CH,
H
2CH2], 2.17 br.s (1H, HC1), 3.28 3.92 m (2H, CH2O), 7.22 7.48 m (5H, Ph)
1
0.88 d (3H, MeC6, 3JH
7.0 Hz), 0.91 s (3H, MeC5-endo), 0.93 t (3H, MeCH2), 1.04 s (3H, MeC5-exo), 1.25 2.05 m [10H, 2CH,
H
2CH2, (CH2)2], 2.16 br.s (1H, HC1), 3.25 3.81 m (2H, CH2O), 7.20 7.48 m (5H, Ph)
VIIa
VIIb
0.75 1.03 d (12H, Me21C5, MeC6, MeCH2), 1.07 2.05 m [15H, 3CH, 2CH2, (CH2)4], 2.22 t (2H, CH2C C), 7.30 8.15 m (5H, Ph)
0.89 d (3H, MeC6, 3JH
7.0 Hz), 0.91 s (3H, MeC5-endo), 1.03 s (3H, MeC5-exo), 1.60 2.40 m [6H, 2CH and 2CH2], 2.75 br.s
H
(1H, HC1), 7.15 8.12 m (10H, 2Ph)
IXa
IXb
Xa
0.83 s, 0.88 t, 0.92 s (9H. Me2C7, MeCH2), 1.05 s (3H, MeC1), 1.10 2.10 m [16H, OH, CH, 3CH2, (CH2)4], 2.21 t (2H, CH2C C)
0.86 s, 0.98 s, 1.08 s (9H, Me2C7, MeC1), 1.06 2.40 m (8H, OH, CH, 3CH2), 7.20 7.48 m (5H, Ph)
0.84 s, 0.88 t and 0.90 s (9H, Me2C7, MeCH2), 0.98 s (3H, MeC1), 1.02 2.07 m [15H, CH, 3CH2, (CH2)4], 2.23 t (2H, CH2C C), 3.24 s (3H,
MeO)
Xb
0.84 s, 0.89 t, 0.91 s [9H, Me2C7, Me(CH2)5], 1.00 s (3H, MeC1), 1.11 t (3H, MeCH2), 1.15 2.10 m [15H, CH, 3CH2, (CH2)4], 2.22 t (2H,
CH2C C), 3.32 3.87 m (2H, CH2O)
Xc
Xd
Xe
0.83 s, 0.89 s, 0.90 t, 1.02 s (15H, Me2C7, 2MeCH2, MeC1), 1.03 2.15 m [19H, CH, 3CH2, (CH2)2, (CH2)4], 2.21 t (2H, CH2C C),
0.89 s, 0.98 s and 1.03 s (9H, Me2C7, MeC1), 1.10 2.45 m (7H, CH, 3CH2), 3.34 s
(3H, MeO), 7.20 7.52 m (5H, Ph)
0.91 c, 1.00 c, 1.08 c (9H, Me2C7, MeC1), 1.10 2.50 m (7H, CH and 3CH2), 1.19 t (3H, MeCH2), 3.35 3.85 m (2H, CH2O), 7.17 7.50 m
(5H, Ph)
Xf
XIa
0.88 1.10 m (12H, Me2C7, MeCH2, MeC1), 1.10 2.50 m [11H, CH, 3CH2, (CH2)2], 3.30 3.80 m (2H, CH2O), 7.12 7.50 m (5H, Ph)
0.88 t (3H, MeCH2), 0.89 s, 0.96 s, 1.10 s (9H, Me2C7, MeC1), 1.10 2.10 m [15H,
CH, 3CH2, (CH2)4], 2.20 t (2H, CH2C C), 7.26 8.15 m (5H, Ph)
XIb
1.00 s, 1.11 s, 1.26 s (9H, Me2C7, MeC1), 1.28 2.80 m (7H, CH and 3CH2), 7.19 8.12 m (10H, 2Ph)

Table 2. Characteristics of compounds Va, b, VIa f, VIIa, b, IXa, b, Xa f, XIa, b
Found, %
Calculated, %
M
20
20
Compd. Yield,
bp, C (p, mm
Hg), mp,
d
nD20
Formula
no.
%
C
C
H
C
H
found
calculated
2
Va
Vb
81
84
79
72
69
74
71
65
78
64
68
80
67
71
74
81
75
82
63
78
104 105 (5 10 )
72 73
90 91 (5 10 )
0.9187
1.4925
82.61
85.16
82.64
82.70
83.12
85.12
85.11
85.21
82.11
83.91
82.50
85.11
82.59
82.77
83.04
85.13
85.18
85.20
82.04
83.84
11.58
8.77
11.70
11.80
12.07
9.10
9.40
9.83
9.35
7.43
11.63
8.81
11.71
11.84
12.06
9.04
9.41
9.84
9.43
7.33
C18H30O
C18H22O
C19H32O
C20H34O
C22H38O
C19H24O
C20H26O
C22H30O
C25H34O2
C25H26O2
C18H30O
C18H22O
C19H32O
C20H34O
C22H38O
C19H24O
C20H26O
C22H30O
C25H34O2
C25H26O2
82.38
84.99
82.55
82.73
82.95
85.03
85.06
85.11
81.92
83.76
82.38
84.99
82.55
82.73
82.95
85.03
85.06
85.11
81.92
83.76
11.52
8.72
11.67
11.87
12.02
9.01
9.28
9.74
9.35
7.31
11.52
8.72
11.67
11.87
12.02
9.01
9.28
9.74
9.35
7.31
255.8
244.4
271.4
281.7
311.6
260.3
271.6
304.3
358.3
347.1
254.6
245.3
269.3
282.0
310.1
257.8
270.4
303.1
359.3
350.4
262.4
254.4
276.5
290.5
318.5
268.4
282.4
310.5
366.5
358.5
262.4
254.4
276.5
290.5
318.5
268.4
282.4
310.5
366.5
358.5
2
VIa
VIb
VIc
VId
VIe
VIf
VIIa
VIIb
IXa
IXb
Xa
Xb
Xc
Xd
Xe
Xf
XIa
XIb
1.0171
0.9776
0.8823
1.0356
1.0145
1.1380
1.1116
1.4760
1.4735
1.4745
1.5465
1.5375
1.5310
1.5210
2
100 101 (5 10 )
2
127 128 (5 10 )
2
103 104 (5 10 )
2
111 112 (5 10 )
2
128 129 (5 10 )
2
175 176 (5 10 )
95 96
2
103 104 (5 10 )
1.0053
1.0668
1.0457
1.0075
0.9345
1.0382
0.9974
1.0681
1.1165
1.4840
1.5600
1.4795
1.4755
1.4730
1.5505
1.5410
1.5305
1.5165
2
125 126 (5 10 )
2
95 96 (5 10 )
2
98 98 (5 10 )
2
108 109 (5 10 )
2
102 103 (5 10 )
2
105 106 (5 10 )
2
115 116 (5 10 )
2
186 187 (5 10 )
131 132

186
DIKUSAR et al.
were registered on spectrometers Tesla BS-567A
(100 MHz) and Bruker AC-300 (300 MHz) from
2 5% solutions in (CD3)2SO, internal reference
TMS. The 13C NMR spectra were recorded on
spectrometer Tesla BS-587 A at operating frequency
20 MHz. Mass spectra were taken on Chrommass
GC/MS Hewlett Packard 5890/5972 instrument,
column HP-5MS (70 eV), eluent dichloromethane.
UV spectra were registered on spectrophotometer
Specord UV Vis from solutions in methanol of con-
iodide or butyl bromide and 3 ml of HMPA. With
methyl and ethyl iodides the reaction was completed
in 18 h at 20 C. With butyl bromide the reaction
mixture was refluxed for 50 h under argon atmo-
sphere. To the reaction mixture was added 100 ml of
hexane, the organic solution was washed with water
and 30% solution of NaOH, dried on CaCl2, the
solvent was removed, and compounds VIa e, Xa e
were distilled in a vacuum.
2-exo-[1-Octynyl (VIIa) or 2-phenyl-1-ethynyl
(VIIb)]2-endo-benzoyloxy-5,5,6- or ( )-2-endo-[1-
octynyl (XIa) or 2-phenyl-1-ethynyl (XIb)]-2-exo-
benzoyloxy-1,7,7-trimethylbicyclo[2.2.1]heptanes.
To a solution containing 0.01 mol of lithium alcoho-
lates IVa, b, VIIIa, b was added in one portion
0.012 mol of benzoyl chloride, the mixture was
stirred for 3 h and left overnight. Then 100 ml of
water was added, the reaction products were extracted
into hexane, the organic layer was washed with
water, with saturated water solution of NaHCO3, and
dried on CaCl2. The solvent was removed. Benzoates
VIIa, XIa were purified by vacuum distillation,
compounds VIIb, XIb were recrystallized from
hexane.
2
centration 1.10 M for compounds Va, VI a c, IXa,
4
Xa c or 1.10 M for compounds Vb, VId f, VIIa,
b, IXb, Xd f, XIa, b. Molecular weight of com-
pounds was measured cryoscopically in benzene. For
column chromatography was used neutral Al2O3 of II
grade Brockmann activity.
Butyllithium was prepared along procedure [14].
2-exo-[1-Octynyl (IVa) or 2-phenyl-1-ethynyl
(IVb)]-2-endo-lithiumoxy-5,5,6-or ( )-2-endo-[1-
octynyl (VIIIa) or 2-phenyl-1-ethynyl (VIIIb)]-2-exo-
lithiumoxy-1,7,7-trimethylbicyclo[2.2.1]heptanes. To
a cooled to 40 20 C solution of 0.013 mol of
alkyne Ia, b in 20 ml of anhydrous tetrahydrofuran
was added at vigorous stirring within 0.5 h 0.011 mol
of butyllithium in hexane. The mixture was stirred at
this temperature for 1 h, and then 0.01 mol of ketone
IIIa, b was added, the temperature was raised to
20 C within 1 h, and the stirring was continued for
3 h more. Then the reaction mixture was left over-
night. Compounds IVa, b and VIIIa, b were used as
obtained without isolation.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 2 2002

CAMPHOR AND ISOCAMPHANONE IN THE SYNTHESIS
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