Synthesis of amino acid derivatives of 4-(1-adamantyl)benzoic acid obtained by transition metal ion catalyzed oxidation of 4-(1-adamantyl)toluene

Article abstract of DOI:10.1016/j.tetlet.2003.11.057

An efficient synthesis of 4-(1-adamantyl)benzoic acid based on transition metal ion catalyzed oxidation of 4-(1-adamantyl)toluene has been developed. As a catalytic system, cobalt-manganese bromide with addition of manganese acetate was used. A series of

Full text of DOI:10.1016/j.tetlet.2003.11.057

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 711–714
Synthesis of amino acid derivatives of 4-(1-adamantyl)benzoic acid
obtained by transition metal ion catalyzed oxidation of
4
-(1-adamantyl)toluene
Sergey V. Krasnikov, Tatiana A. Obuchova, Oleg A. Yasinskii and Konstantin V. Balakin*
Yaroslavl State Technological University, Moskovskii Prospect 88, Yaroslavl 150023, Russia
Received 15 September 2003; revised 6 November 2003; accepted 14 November 2003
Abstract—An efficient synthesis of 4-(1-adamantyl)benzoic acid based on transition metal ion catalyzed oxidation of 4-(1-ada-
mantyl)toluene has been developed. As a catalytic system, cobalt–manganese bromide with addition of manganese acetate was used.
A series of amino acid derivatives of 4-(1-adamantyl)benzoic acid was then synthesized and characterized. These derivatives are
novel intermediates potentially useful in the design of therapeutically active peptidomimetics with improved pharmacokinetic and
pharmacodynamic parameters.
Ó 2003 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
Numerous derivatives of adamantane have been
reported as biologically active agents useful in the
therapeutic treatment of various human pathological
conditions. Among them are well-known drugs, such as
Rimantadine, Memantine, Adapalene, and Adatanserin.
The growing interest in adamantanes is highlighted by
the development of compounds that contain in their
structures the adamantane moiety and a natural or
modified amino acid residue. Such peptidomimetic
H
H
N
O
N
N
H
OH
O
O
N
1
H
O
O
H
compounds were reported as promising anxiyolytics
1
N
(
e.g., PD-134308 1 now entering phase II clinical trials),
agents for treatment of osteoporosis (e.g., compound
), and analgesics (e.g., compound 3 ). The introduc-
N
N
O
H
O
O
N
2
3
2
2
tion of a bulky lipophilic adamantane moiety leads to an
improvement in the pharmacodynamic and pharmaco-
OH
NH2
3;4
kinetic properties of potential therapeutic agents.
O
H
N
4
-(1-Adamantyl)benzoic acid is a useful intermediate for
N
N
introduction of the adamantane moiety into synthetic
molecules. Synthesis of phenylcarboxylic acid adaman-
tane compounds have been reported using cobalt ion
H
O
3
5
catalyzed oxidation of phenylalkyladamantanes. How-
ever, to the best of our knowledge, no biologically active
derivatives of 4-(1-adamantyl)benzoic acid have been
reported to date. In this work, we have developed an
efficient synthetic strategy for the synthesis of 4-(1-
adamantyl)benzoic acid and its amino acid derivatives.
Keywords: Transition metal; Catalytic oxidation; Cobalt–manganese
bromide catalyst; Adamantane derivatives.
*
Corresponding author. Tel.: +7-095-4834-144; fax: +7-095-5760-155;
e-mail: kvb@chemdiv.com
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.057

712
S. V. Krasnikov et al. / Tetrahedron Letters 45 (2004) 711–714
Table 1. Amino acid derivatives of 4-(1-adamantyl)benzoic acid
2
. Results and discussion
Compound
R
Yield (%)
One of the most effective methods for the synthesis of
the aromatic oxygen-containing compounds, particu-
larly monocarboxylic acids, is a liquid-phase oxidation
of alkylbenzenes with molecular oxygen in the presence
of transition metal (TM) ions and promoting additives.
These reaction conditions are generally more efficient
in comparison to other self-oxidation catalysts, with
respect to being able to control the selectivity, and
allowing easy separation of the reaction products from
the catalyst. In addition, this method is also superior to
the so-called ꢀstoichiometricꢁ methods, which use per-
7
8
CH
3
85
90
3 2
CH(CH )
9
CH2
75
77
1
0
1
1
1
2
CH
(CH
2
CH(CH
SCH
3
3
)
2
90
68
2
)
2
6
manganates and dichromates. This method provides
CH2
higher yields of the desired products, reduced quantities
of the reagents are required, and the absence of addi-
tional inorganic side products makes purification easier.
Oxidation using nitrous acid, while providing the
products in good yields, can lead to undesired nitration
1
1
3
4
82
70
N
H
7
N
side products.
CH2
NH
Recently, we have developed an efficient method for the
oxidation of alkylbenzenes with molecular oxygen in the
presence of a cobalt–manganese bromide catalyst with
8
14
the addition of manganese acetate. In this work, we
9
obtained 4-(1-adamantyl)benzoic acid 5 from 4-(1-
generation of peroxide radicals, or by chain cleavage
15
by the metal ions. It is known that liquid-phase oxi-
dation in protic solvents, such as acetic acid, favors the
second mechanism because of the high catalyst con-
adamantyl)toluene 4 in 90–95% yield (Scheme 1). In
comparison to the previously reported synthesis of 4-(1-
adamantyl)benzoic acid, where a cobalt-bromide cata-
15
centration that can be obtained. In this instance, the
substrate to be oxidized interacts preferentially with the
highest valence form of the TM ions with the generation
of a free radical. On the other hand, it is well established
that the usual reactivity of a-C–H bonds in reactions that
proceed via free radicals, tertiary > secondary > primary,
proceeds in an inverse manner to the liquid-phase
oxidation of alkylbenzenes in acetic acid with addition
5
lyst was used, our method provides better yields, higher
efficiency (significantly reduced consumption of cata-
lyst), and synthetic convenience. The acid 5 was quan-
titatively converted into the chloride 6 by the treatment
10
with thionyl chloride. The target amino acid deriva-
tives 7–15 were then obtained using the Schotten–
11
12
Baumann reaction as pure (R)- and (S)- or mixed
R,S)-stereoisomers with good yields (Scheme 1, Table
). The enantiomeric purities of the resulting com-
(
of Co(OAc)
2
Æ4H O as the catalyst, and acetaldehyde or
2
16
1
NaBr as a promoter. Possible reasons for the inversion
of reactivity of C–H bonds may be the multistage
character and kinetic control of this reaction. The
radicals generated undergo further oxidative conver-
sions.
1
pounds were confirmed by H NMR spectroscopy
recorded in the presence of a chiral shift reagent by the
method described in the literature.
17
13
Depending on the reaction conditions, oxidation in the
presence of TM ions can proceed predominantly in one
of two possible directions: chain elongation through the
The oxidation kinetics of para-substituted toluenes
under the described conditions were studied in our
a
b
CH3
COOH
4
5
O
COOH
c
N
7-14
H
R
COCl
d
O
6
COOH
N
15
Scheme 1. Reagents and conditions: (a) O
(c,d) amino acid, 2 N NaOH, H O/1,4-dioxane, 68–90%.
2
, NaBr, Mn(OAc)
2
, Co(OAc)
2
, CH
3
2 6 6
COOH/1,4-dioxane, 90 °C, 95%; (b) SOCl , C H , quantitative yield;
2

S. V. Krasnikov et al. / Tetrahedron Letters 45 (2004) 711–714
713
8
recent work. Specifically, it was shown that in the first
7. Weissermel, K.; Arpe, H.-J. Industrial Organic Chemistry,
nd ed.; Chemie: Weinheim, NY, 1993; Chapter 14.
2
stages of oxidation, an ionic interaction occurs between
the catalyst and the initial toluene derivative. The
proposed mechanism of oxidation with TM ions in
acetic acid is in full agreement with our experimental
data. Thus upon oxidation of 4-(1-adamantyl)toluene 4
in the presence of a cobalt–manganese bromide catalyst
with the addition of manganese acetate, 4-(1-adaman-
tyl)benzoic acid 5 was obtained via formation of a
radical at the methyl group, in high yield. In the
proposed mechanism, the C–H bonds of the adaman-
tane moiety do not participate in the radical pathway
although they can be easily oxidized by many other
oxidizing agents.
8
. (a) Obuchova, T. A.; Kluev, I. V.; Krasnikov, S. V.;
Betnev, A. F. RU Patent 2183620, 2002; Der. Abstr.
C2002-581461; (b) Betnev, A. F.; Obuchova, T. A.; Kluev,
I. V.; Krasnikov, S. V. Izv. Vuzov. Khim. Techn. (Proc.
Inst. Higher Edu.: Chem. Technol.) 2000, 43, 73–75.
9
. 4-(1-Adamantyl)benzoic acid 5: white crystals with mp
1
3
08–310 °C; H NMR (CDCl
3
, 400 MHz): d 1.78 (m, 6H),
1.92 (m, 6H), 2.12 (m, 3H), 7.38 (d, 2H, J ¼ 7.8 Hz), 7.88
(d, 2H, J ¼ 7.8 Hz), 12.30 (s, 1H); R 0.66 (toluene/
f
petroleum ether/acetone/acetic acid, 16:16:10:1). Anal.
Calcd for C17
20 2
H O : C, 79.7; H, 7.8; O, 12.5. Found: C,
7
9.5; H, 7.7; O, 12.6.
1
1
0. 4-(1-Adamantyl)benzoic acid chloride 6 was quantitatively
obtained from acid 5 by reaction with thionyl chloride in
benzene and was used in the next step without purification.
1. Satisfactory analytical data ( H NMR, mass spectra,
elementary analysis) were obtained for all new com-
In summary, cobalt–manganese bromide with addition
of manganese acetate in acetic acid is a mild and efficient
system for the selective catalytic oxidation of substituted
1
pounds. For example: (2S)-[4-(1-adamantyl)phenylcarb-
1
18
toluenes. Using this approach, we developed an effi-
cient synthetic route to 4-(1-adamantyl)benzoic acid 5.
A series of 4-(1-adamantyl)benzoylated amino acids
were then prepared with 60–80% overall yields starting
from 4-(1-adamantyl)toluene 4. Biological evaluation
of compounds 7–15 is currently in progress and will
be reported elsewhere.
oxamido]-3-methylbutanoic acid 8: mp 215–218 °C;
H
NMR [DMSO-d +CCl (1:3), 500 MHz]: d ¼ 1.00 (d, 6H,
6
4
J ¼ 6.0 Hz), 1.78 (m, 6H), 1.92 (m, 6H), 2.12 (m, 3H), 2.22
(
m, 1H), 4.40 (dd, 1H, J ¼ 6.7, 6.4 Hz), 7.37 (d, 2H,
J ¼ 7.8 Hz), 7.74 (m, 1H), 7.80 (d, 2H, J ¼ 7.8 Hz); EIMS:
þ
m=z 355 (9%) [M] ; R
f
0.36 (toluene/petroleum ether/
acetone/acetic acid, 16:16:10:1). Anal. Calcd for
: C, 74.3; H, 8.2; N, 3.9; O, 13.6. Found: C,
4.4; H, 8.0; N, 4.1; O, 13.3. (2S,R)-[4-(1-Adamantyl)phe-
nylcarboxamido]-3-phenylpropanoic acid 9: mp 108–
22 3
C H29NO
7
1
1
1
10 °C; H NMR [DMSO-d
.78 (m, 6H), 1.93 (m, 6H), 2.12 (m, 3H), 3.10 (dd, 1H,
6 4
+CCl (1:3), 500 MHz]: d
3
. Experimental protocol for the oxidation of
-(1-adamantyl)toluene
4
J ¼ 14.8, 10.0 Hz), 3.20 (dd, 1H, J ¼ 14.8, 4.6 Hz), 4.65 (m,
H), 7.15 (m, 1H), 7.23 (m, 2H), 7.28 (m, 2H), 7.36 (d, 2H,
1
A mixture of cobalt acetate (0.525 g, 2.11 mmol), man-
ganese acetate (0.059 g, 0.24 mmol), sodium bromide
J ¼ 7.8 Hz), 7.73 (d, 2H, J ¼ 7.8 Hz), 8.12 (m, 1H); EIMS:
þ
m=z 403 (6%) [M] ; R 0.39 (toluene/petroleum ether/
f
(
4
1
0.24 g, 2.33 mmol), and 4-(1-adamantyl)toluene (10.71 g,
7.4 mmol) in 95% aqueous acetic acid (200 mL) and
,4-dioxane (20 mL) were stirred in a three-necked
acetone/acetic acid, 16:16:10:1). Anal. Calcd for
: C, 77.3; H, 7.2; N, 3.5; O, 12.0. Found: C,
C
26
H29NO
3
7
7.0; H, 7.2; N, 3.3; O, 12.1.
1
1
2. Steiger, R. J. Org. Chem. 1944, 92, 396.
3. Coxon, J. M.; Cambridge, J. R. A.; Nam, S. G. C. Org.
Lett. 2001, 3, 4225–4227.
4. Emanuel, N. M.; Denisov, E. T.; Maizus, S. K. Chain
Oxidation Reactions of Hydrocarbons in Liquid Phase;
Nauka: Moscow, 1965; p 375.
round-bottomed flask equipped with an oxygen bubbler,
a backflow condenser, a magnetic stirrer, and a ther-
mometer. Oxygen was introduced and the mixture was
allowed to react for 2 h at a temperature of 90 °C. Then
the reaction mixture was concentrated by evaporating
1
1
50 mL of solvent. Cooled water (100 mL) was added to
1
5. Obuchova, T. A.; Mironov, G. S. Izv. Vuzov. Khim. Techn.
(Proc. Inst. Higher Edu.: Chem. Technol.) 1991, 34, 3–
13.
the cooled reaction mixture, and the precipitated crys-
tals were filtered and dried to give 11.53 g (95%) of pure
4
-(1-adamantyl)benzoic acid.
16. Obuchova, T. A.; Basaeva, N. N.; Mironov, G. S.;
Kuznetsov, M. M.; Bondarenko, A. V. Petrochemistry
1
978, 28, 573–578.
1
7. (a) Dessau, R. H.; Shih, S.; Heiba, E. I. J. Am. Chem. Soc.
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G. S. Zh. Org. Khim. (J. Org. Chem.) 1992, 28, 756–759;
(d) Simkin, B. Y.; Sheikhet, I. I. Quantum-Chemical
and Statistical Theory of Solutions; Khimiya: Moscow,
1989; p 252.
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6