Preparative Synthesis of Functionally Substituted Esters of 1-Adamantanecarboxylic Acid

Article abstract of DOI:10.1023/A:1023356219642

A procedure was developed for preparing 1-adamantanecarboxylic acid esters functionally substituted in the alcoholic moiety.

Full text of DOI:10.1023/A:1023356219642

Russian Journal of Applied Chemistry, Vol. 76, No. 1, 2003, pp. 105 107. Translated from Zhurnal Prikladnoi Khimii, Vol. 76, No. 1,
2003, pp. 107 110.
Original Russian Text Copyright
2003 by Kozlov, Dikusar, Potkin.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Preparative Synthesis of Functionally Substituted Esters
of 1-Adamantanecarboxylic Acid
N. G. Kozlov, E. A. Dikusar, and V. I. Potkin
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus
Received July 2, 2002
Abstract A procedure was developed for preparing 1-adamantanecarboxylic acid esters functionally substi-
tuted in the alcoholic moiety.
Compounds of the adamantane series exhibit high
and diverse biological activity. Effective drugs based
on adamantane have been developed, such as Midan-
tane, Memantine, Gludantan, Remantadine, and Ada-
promine [1]. Some of adamantane derivatives exhibit
antiviral, curare-like, myorelaxing, anti-choline este-
rase, psychostimulating, neurotropic, and local anes-
thetic activity [2]; compounds with a high surface
activity were also found [3]. The main synthetic route
to adamantane derivatives involves chemical modifi-
catiomn of substituents in the hydrocarbon frame-
work. Nitrogen-containing adamantane derivatives
have been studied most comprehensively [4, 5].
taining biologically active compounds is preparation
of esters. In this case, it is possible to combine in one
molecule an adamantane moiety with other functional
groups, e.g., aromatic, acetylenic, or bicyclic [6].
Here we report on a new convenient route to func-
tionally substituted esters of 1-adamantanecarboxylic
acid, involving the reactions of 1-adamantylcarbonyl
chloride I with alcohols II XII in diethyl ether in
the presence of pyridine [7]. Esters XIII XXIII are
formed under mild conditions (room temperature). No
prolonged stirring, heating, or precipitation is re-
quired; the reactants can be mixed in any order. The
reaction, performed in sealed vessels, is complete in
24 36 h; the yield of esters is 65 83%.
One of promising routes to new adamantane-con-
O
Py
Ad-1
(CH ) OH
H
H
+
(CH )O
n
2
n
2
COCl
Me
IIa IIc
XIIIa XIIIc
I
II, XIII,
n =1 (a), 2 (b), 3 (c)
H
H
H
H
Me
Py
I,
Py
I,
R
R
OH
Ad-1
O
H
Ad-1
O
H
OH
III
O
O
XIV
IVa, IVb
XVa, XVb
IV, XV, R = H (a), Me (b)
Me
Me
7 Me
Me
6
4
Me
5
Py
I,
Py
I,
Me
1
Me
Me
Me
1
2
OH
O
2
6
H
H
3
4
Ad-1
3O
OH
1-Ad
XVI
O
5
V
VI
O
XVII
1070-4272/03/7601-0105$25.00 2003 MAIK Nauka/Interperiodica

106
KOZLOV et al.
OH
H
Ad-1
O
H
Py
I,
Py
I,
Ad-1
O
O
O
OH
H
H
VII
VIII
XVIII
XIX
O
Ad-1
OH
O
Py
I,
O
Py
I,
Ad-1
OH
O
OH
OH
IX
XX
X
XXI
O
O
OH
Ad-1
Ad-1
OH
O
O
O
O
Me
Py
I,
Py
I,
Me
OH
XI
OH
XXII
O
O
XXIII
XII
1
1
Primary alcohols (IIa IIc, IX), secondary alcohols
(III VIII), and phenols (X XII) are readily esterified
with chloride I. Dihydric phenols X and XI form
momoesters only, even at the reactant ratio I : (X or
XI) = 3 : 1. Tertiary alcohols (e.g., 2-methyl-2-prop-
anol or 2-methyl-3-butyn-2-ol) do not form the corre-
sponding esters even under severe conditions (pro-
longed refluxing in dioxane at 100 102 C in the pres-
ence of pyridine).
(1697 cm ) and C O C (1110 cm ) groups.
1
The H NMR spectra of all the esters XIII XXIII
contain multiplets at 1.6 (6H), 1.9 (6H), and 2.1 ppm
(3H), typical of 1-substituted adamantane derivatives.
Compounds XIIIa XIIIc and XIV containing termi-
nal acetylenic groups also give a proton signal at
2.0 2.4 ppm. The CH O proton signals in the spectra
2
of XIIIa XIIIc and XX are observed at 4.1 ppm, and
in esters XV XIX derived from alicyclic alcohols the
-CH proton in the alcoholic residue gives a signal at
4.7 4.9 ppm. The spectra of these esters also contain
signals characteristic of cyclohexane (XV), menthane
[XVI; a doublet of the C CH protons at 0.74 ppm
( J 1.6 Hz) and a doublet of two methyl groups in the
1-Adamantanecarboxylic acid esters are colorless
viscous liquids (XIIIa, XVb, XVI) or crystalline sub-
stances (XIIIb, XIIIc, XIV, XVa, XVII XXII); their
characteristics are listed in the table.
1
3
3
The IR and NMR spectra of the synthesized esters
are consistent with their structure. The IR spectra
contain stretching vibration bands of the C=O (1727
3
isopropyl substituent at 0.94 ppm ( J 6.7 Hz)], and
camphane [XVII, XVIII; singlets of three methyl
1
1
7
5; for XXIII, 1742 cm ) and C O (1225 15 and
groups at C (0.8 ppm) and C (1.0 ppm) atoms]. The
aryl protons in XXI XXIII are manifested at 6.4
7.5 ppm. Also, the spectrum of XXIII exhibits a CHO
1
1070 15; for XXIII, 1290 and 1155 cm ) groups.
The spectra of acetylenic derivatives XIIIa XIIIc and
XIV also contain absorption bands at 3280 25
singlet at 9.9 ppm and an OCH singlet at 3.9 ppm.
3
1
( C H) and 2150 15 cm (C C). Aromatic esters
XXI XXIII exhibit C H absorption bands at 3090,
3070, 3030 5; 858, 777, 767, and 680 (XXI); 830
and 800 (XXII); 865 and 785 cm (XXIII), and also
EXPERIMENTAL
1
The IR spectra were recorded on a Protege-460
IR Fourier spetrophotometer (Nicolet) from thin films
(XIIIa, XVb, XVI) or KBr pellets. The H NMR
spectra were recorded on a Tesla BS-567A spectrom-
eter (100 MHz) from 5% solutions in CDCl , with
the bands belonging to the aromatic ring at 1604 and
1
1487 (XXI); 1600 and 1511 (XXII); 1601, 1593, and
1
1509 cm (XXIII). The spectra of phenols XXI and
3
XXII contain O H absorption bands at 3375 (XXI)
1
TMS as internal reference.
and 3445 cm (XXII), and also C OH bands at
1
1065 5 cm . The IR spectrum of aromatic methoxy
The molecular weight was determined by cryos-
copy in benzene.
aldehyde XXIII contains the bands of the HC=O
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 76 No. 1 2003

PREPARATIVE SYNTHESIS OF FUNCTIONALLY SUBSTITUTED ESTERS
Properties of esters XIII XXIII
107
Found, %
Calculated, %
M
Ester
Yield, % mp,
C
Formula
C
H
C
H
found
214.1
calculated
1.0791*
1.5060
XIIIa
79
77.28
8.56
C14H18O2
77.03
8.31
218.3
XIIIb
XIIIc
XIV
77
83
81
70
48 49
56 57
46 47
29 30
77.84
78.44
77.93
78.13
8.95
9.19
8.90
C15H20O2
C16H22O2
C15H20O2
C17H26O2
77.55
78.01
77.55
77.82
8.68
9.00
8.68
9.99
225.8
239.0
227.4
249.3
232.3
246.3
232.3
262.4
XVa
10.18
1.0409*
1.5025
1.0237*
1.4990
XVb
XVI
80
78
78.45
79.50
10.41
10.93
C18H28O2
78.21
79.19
10.21
10.76
262.9
306.7
276.4
318.5
C21H34O2
XVII
XVIII
XIX
XX
XXI
82
84
72
82
65
68
79
176 177
145 146
172 173
82 83
107 108
179 180
118 119
80.03
80.01
80.34
80.88
75.22
75.21
72.71
10.25
10.32
9.85
10.12
7.65
C21H32O2
C21H32O2
C21H30O2
C23H34O2
C17H20O3
C17H20O3
C19H22O4
79.70
79.70
80.21
80.65
74.97
74.97
72.59
10.19
10.19
9.62
10.00
7.40
303.2
308.6
307.0
330.1
260.4
262.3
303.1
316.5
316.5
314.5
342.5
272.3
272.3
314.4
XXII
XXIII
7.60
7.11
7.40
7.05
20
20
* Numerator, d ; denominator, n
.
20
D
Column chromatography was performed with neu-
tral alumina, Brockmann grade II.
(2) Dihydric phenols form monoesters only; ter-
tiary alcohols do not undergo esterification.
1-Adamantanecarboxylic acid chloride I was pre-
pared by refluxing 1-adamantanecarboxylic acid with
ACKNOWLEDGMENTS
a 1.5-fold excess of SOCl in benzene [5].
2
The study was financially supported by the Bela-
russian Republican Foundation for Basic Research
(project no. Kh 03-079) and INTAS (grant 99-00806).
1-Adamantanecarboxylic acid esters XIII XXIII.
Anhydrous pyridine (3.5 mmol) was added to a solu-
tion of 3 mmol of chloride I and 3 mmol of alcohols
or phenols II XII in 70 ml of absolute diethyl ether.
The mixture was slightly shaken and allowed to stand
at 18 23 C for 24 36 h. The precipitate of pyridine
hydrochloride was filtered off and washed with 30 ml
of diethyl ether; the combined filtrates were washed
with water and saturated aqueous solution of sodium
hydrogen carbonate. The ether solution was dried over
REFERENCES
1. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
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kologiya adamantanov (Pharmacology of Adaman-
tanes), Volgograd: Volgograd. Med. Akad., 2001.
CaCl , the solvent was distilled off, and the residue
was dried in a vacuum. Ethers XIIIa, XVb, and XVI
3. Vashkevich, E.V., Yurashevich, N.Ya., Kozlov, N.G.,
et al., Zh. Prikl. Khim., 2001, vol. 74, no. 11, pp. 1833
1839.
2
were purified by column chromatography on Al O ,
2
3
eluent hexane. Compounds XIIIb, XIIIc, XIV, XVa,
and XVII XXIII were purified by low-temperature
crystallization from hexane.
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tions), Moscow: Nauka, 1989.
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Molecules, New York: Dekker, 1976.
CONCLUSIONS
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(1) Functionally substituted primary and secondary
alcohols and phenols are readily esterified under mild
conditions with 1-adamantanecarboxylic acid chloride
in the presence of pyridine.
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RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 76 No. 1 2003