Synthesis of 3,5-dimethyladamantan-1-ol by reaction of 1,3- dimethyladamantane with bromotrichloromethane and water in the presence of manganese complexes

Article abstract of DOI:10.1134/S1070428014010059

3,5-Dimethyladamantan-1-ol was synthesized in 79% yield by reaction of 1,3-dimethyladamantane with bromotrichloromethane and water in the presence of manganese salts and complexes activated by pyridine.

Full text of DOI:10.1134/S1070428014010059

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 1, pp. 25–28. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © R.I. Khusnutdinov, K.S. Kislitsina, N.A. Shchadneva, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 1,
pp. 33–36.
Synthesis of 3,5-Dimethyladamantan-1-ol by Reaction
of 1,3-Dimethyladamantane with Bromotrichloromethane
and Water in the Presence of Manganese Complexes
R. I. Khusnutdinov, K. S. Kislitsina, and N. A. Shchadneva
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia
e-mail: ink@anrb.ru
Received July 31, 2013
Abstract—3,5-Dimethyladamantan-1-ol was synthesized in 79% yield by reaction of 1,3-dimethyladamantane
with bromotrichloromethane and water in the presence of manganese salts and complexes activated by
pyridine.
DOI: 10.1134/S1070428014010059
Adamantane and its derivatives are widely used for
the preparation of valuable compounds needed for
various branches of industry. Due to high thermal
stability adamantane derivatives are used to obtain
heat-resistant polymers. They are also starting mate-
rials in the manufacture of oils, hydraulic fluids, and
antimicrobial additives for lubricants. An important
field of application of adamantane and its derivatives is
the synthesis of drugs with antiviral and neurotropic
activity. A useful adamantane derivative is 3,5-di-
methyladamantan-1-ol (I) which is a starting com-
pound for the synthesis of 3,5-dimethyladamantan-1-
amine, the active component of Memantine, an anti-
Alzheimer drug also efficient in the treatment of other
central nervous system disorders at early stages [1–4].
These procedures are not free from such disadvantages
as the use of aggressive concentrated inorganic acids,
complex equipment due to high corrosivity of initial
reactants, and formation of large amounts of acid
wastes and wastewater to be disposed.
Taking into account practical importance of 3,5-di-
methyladamantan-1-ol (I), we set ourselves the task of
developing a new efficient one-pot procedure for the
preparation of compound I using metal complex
catalysis. In order to convert 1,3-dimethyladamantane
(II) into alcohol I, we tried the system CBrCl3–H2O–
[Mn] {where [Mn] = Mn(OAc)3 ·4H2O, Mn2(CO)10,
Mn(acac)3}. As shown previously [12], such systems
generate hypobromous acid HOBr.
GLC analysis of the reaction mixture showed that
the formation of 3,5-dimethyladamantan-1-ol (I) in the
reaction of 1,3-dimethyladamantane (II) with CBrCl3
and water in the presence of Mn(acac)3 is a stepwise
process (Scheme 1). In the first step 1,3-dimethyl-
adamantane (II) reacts with CBrCl3 to give 1-bromo-
Most methods for the preparation of 3,5-dimethyl-
adamantan-1-ol (I) are based on the bromination of
1,3-dimethyladamantane (II), followed by hydrolysis
of 1-bromo-3,5-dimethyladamantane (III) thus formed
in the presence of inorganic and organic bases [5–11].
Scheme 1.
[Mn]
CBrCl3
+
H2O
CHCl3
Me
+ HOBr
Me
Me
Mn(acac)3, pyridine
140°C, 5 h
H2O
CBrCl3
+
–CHCl3
Me
Br
Me
HO
Me
II
III
I
25

KHUSNUTDINOV et al.
26
3,5-dimethyladamantane (III). Presumably, this reac-
tion follows a radical mechanism and is initiated by
hypobromous acid whose concentration was estimated
by iodometric titration at 9.8 mg/mL in 2 h and
5.4 mg/mL in 5 h. Simultaneously, bromide III under-
goes hydrolysis to alcohol I, and the concentrations of
I and III in the reaction mixture become equal in 1 h
after the reaction started. According to the GLC and
GC/MS data, the reaction mixture also contained
chloroform, which indicated participation of CBrCl3 in
the formation of bromide III. After 1 h, the concen-
trations of CHCl3 and CBrCl3 were comparable. No
reaction occurred in the absence of CBrCl3. To com-
plete the hydrolysis of III to alcohol I, heating for
a longer time (5 h) is necessary.
cyanopyridines, and 2,2′-bipyridine are also capable of
activating manganese complexes, but their activating
effect is weaker. The reaction was not accompanied by
bromination or hydroxylation of the methyl groups in
1,3-dimethyladamantane (II).
The reactions were carried out with 1,3-dimethyl-
adamantane, CBrCl3, Mn(acac)3, H2O, and substituted
pyridine taken at a molar ratio of 100:(125–150):
5:(6000–10000):(200–400) at 130–150°C for 5–6 h.
Under the optimal conditions using Mn(acac)3–pyri-
dine as catalytic system, the major product was 3,5-di-
methyladamantan-1-ol (I) whose yield attained 79%,
the conversion of 1,3-dimethyladamantane (II) being
97%. As by-products (~5%) we identified by GC/MS
dibromo derivatives of 1,3-dimethyladamantane and
isomeric diols. The results of the synthesis of 3,5-di-
methyladamantan-1-ol (I) under different conditions
are collected in Table 1. We have developed a proce-
dure for quantitative determination of the yield of I by
GLC analysis of the reaction mixture obtained from
1,3-dimethyladamantane (II), water, and CBrCl3 in the
presence of Mn(acac)3; decane was used as internal
standard.
The conversion of 1,3-dimethyladamantane (II) and
the yield of 3,5-dimethyladamantan-1-ol (I) depended
on the catalyst nature. Among the examined manga-
nese compounds, Mn(acac)3 turned out to be the best
catalyst whose highest activity was attained when
pyridine was added to the reaction mixture. The role of
pyridine is likely to bind hydrogen bromide, and the
resulting pyridine hydrobromide can act as phase-
transfer catalyst.
Further experiments showed that compound I can
also be synthesized using CBr4 instead of CBrCl3.
Under the optimal conditions the conversion of 1,3-di-
methyladamantane II was 65–70%, the yield of 3,5-di-
methyladamantan-1-ol (I) was 35–40%, and 1- and
2-bromo-3,5-dimethyladamantanes were formed in
30% yield (Table 2). The optimal ratio CBr4–II was
The optimal substrate-to-pyridine ratio (1:2) was
determined experimentally. Higher concentration of
pyridine strongly complicates isolation of compound I
from the reaction mixture because of poor layer
separation, so that the yield of the target product
decreases. Apart from pyridine itself, alkylpyridines,
Table 1. Reaction of 1,3-dimethyladamantane (II) with bromotrichloromethane and water in the presence of manganese
compounds (MnLx) and substituted pyridines (Py)
Molar ratio
MnLx–II–CBrCl3–H2O–Py
Temperature, Reaction Conversion
Yield
of I, %
MnLx
Activator
Pyridine
°C
time, h
of II, %
5:100:125:6000:200
5:100:125:10000:400
5:100:125:10000:200
5:100:125:10000:200
5:100:125:6000:400
5:100:125:6000:400
5:100:125:6000:400
5:100:125:6000:400
5:100:125:6000:400
5:100:125:6000:400
5:100:150:300:200
5:100:150:300:200
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn(acac)3
Mn2(CO)10
Mn(OAc)2·4H2O
Mn2(CO)10
Mn(acac)3
Mn(acac)3
Mn(acac)3
140
140
140
150
140
140
140
140
140
140
130
130
5
5
5
6
5
5
5
5
5
5
6
6
96
97
98
88
76
97
74
83
97
83
94
96
79
70
65
50
32
66
43
35
52
47
06
10
Pyridine
Pyridine
Pyridine
2-Methylpyridine
3-Methylpyridine
Pyridine
Pyridine
3-Methylpyridine
4-Methylpyridine
2,2′-Bipyridine
2-Cyanopyridine
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

SYNTHESIS OF 3,5-DIMETHYLADAMANTAN-1-OL
27
Table 2. Synthesis of 3,5-dimethyladamantan-1-ol (I) by reaction of 1,3-dimethyladamantane (II) with carbon tetrabromide
and water in the presence of Mn(acac)3
Molar ratio
Mn(acac)3–II–CBr4–H2O–Py
Temperature, °C
Reaction time, h Conversion of II, %
Yield of I, %
5:100:50:6000:0
5:100:50:6000:400
5:100:100:6000:0
5:100:50:6000:200
5:100:50:6000:0
5:100:100:6000:0
5:100:50:6000:0
140
140
140
150
150
150
140
6
6
6
4
4
6
8
53
55
60
65
67
70
57
40
35
28
37
34
30
40
1 :2. Rise in the concentration of CBr4 resulted in
increased conversion of II, but the fraction of 1- and
2-bromo and dibromo derivatives of 1,3-dimethylada-
mantane increased simultaneously. Addition of pyri-
dine and variation of the conditions had almost no
effect on the reaction course.
(0.5 mmol) of Mn(acac)3, 1.6 g (10 mmol) of 1,3-di-
methyladamantane (II), 1.25 mL (12.5 mmol) of
CBrCl3, 10.8 mL (600 mmol) of water, and 1.6 mL
(20 mmol) of pyridine. The reactor was tightly closed
and heated for 5 h at 140°C. It was then cooled to 20°C
and opened, and the mixture was washed with water
and extracted with ethyl acetate (3×5 mL). The solvent
was removed under reduced pressure, and the residue
was purified by chromatography on silica gel using
hexane–ethyl acetate (first 9:1 and then 7:3) as eluent.
Yield 80% (purity >98%), mp 95–97°C.
Alcohol I was purified from impurities by column
chromatography on silica gel using hexane–ethyl
acetate as eluent.
EXPERIMENTAL
b. A 17-mL high-pressure micro reactor was
charged with 0.18 g (0.5 mmol) of Mn(acac)3, 1.6 g
(10 mmol) of 1,3-dimethyladamantane (II), 1.66 g
(0.5 mmol) of CBr4, 10.8 mL (600 mmol) of water, and
5.3 mL (30 mmol) of CH2Br2. The reactor was tightly
closed and heated for 6 h at 140°C. The mixture was
then treated as described in a. Yield 40%. IR spectrum:
The IR spectra were recorded in KBr or mineral oil
1
13
on a Bruker Vertex 79V spectrometer. The H and C
NMR spectra were measured on a Bruker Avance-400
instrument at 400.13 and 100.62 MHz, respectively,
using CDCl3 as solvent and tetramethylsilane as
internal reference. The mass spectra were obtained on
a Shimadzu GCMS-QP2010Ultra instrument (Supelco
PTE-5 capillary column, 60 m×0.25 mm; carrier gas
helium; injector temperature 260°C; oven temperature
programming from 40 to 280°C at a rate of 8 deg/min;
ion source temperature 200°C; electron impact,
70 eV). The elemental compositions were determined
on a Carlo Erba 1108 analyzer. GLC analyses were
carried out on a Carlo Erba GC 6000 Vega Series 2
chromatograph using a 3-m steel column packed with
15% of PEG-6000 on Chromaton N-AW-HMDS (oven
temperature programming from 50 to 180°C at a rate
of 8 deg/min; carrier gas helium, flow rate 47 mL×
min–1). Calibration factors of 1.01 and 1.41 (relative
to decane used as internal standard) were found for
1,3-dimethyladamantane (II) and 3,5-dimethyladaman-
tan-1-ol (I), respectively.
1
ν 3394 cm–1 (OH). H NMR spectrum, δ, ppm: 0.86–
0.92 m (6H, CH3), 1.23–1.4 m (8H, 4-H, 8-H, 9-H,
10-H), 1.56–1.6 m (2H, 6-H), 1.96–1.98 m (1H, 7-H),
2.17–2.19 m (2H, 2-H), 2.69 s (1H, OH). 13C NMR
spectrum, δC, ppm: 29.02 (C7), 29.98 (CH3), 31.09 (C3,
C5), 42.47 (C8, C10), 43.87 (C6), 50.48 (C2), 51.44 (C4,
C9), 69.81 (C1). Mass spectrum, m/z (Irel, %): 180
(26.0) [M]+, 165 (11.5) [M – 15]+, 123 (100) [M – 57]+,
109 (95.1), 107 (29.0), 81(10.3), 67 (10.9), 55 (16.9),
43 (18.8), 41 (22.4). Found, %: C 79.91; H 11.15.
C12H20O. Calculated, %: C 79.94; H 11.18.
M 180.1515.
This study was performed under financial support
by the Ministry of Education and Science of the
Russian Federation (state contract no. 02.740.11.0631)
and by the President of the Russian Federation
(research grant for young scientists and post-graduate
students no. SP-4426.2013.4).
3,5-Dimethyladamantan-1-ol (I). a. A 17-mL
high-pressure micro reactor was charged with 0.18 g
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KHUSNUTDINOV et al.
7. Taketani, S., Yamaguchi, H., Hara, T., Iwahama, T.,
28
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