Synthesis and reactivity of 3-R-1-adamantyl methyl ketones

Article abstract of DOI:10.1023/A:1013154831862

A general procedure was proposed for synthesizing 3-R-1-adamantyl methyl ketones from the corresponding adamantanecarbonyl chlorides and dimethyl malonate in toluene (benzene) in the presence of sodium hydroxide. Intermediate dimethyl (3-R-1-adamantylcarbonyl)malonates can also be isolated. The resulting ketones were brought into reactions with hydroxylamine and formamide in the presence of formic acid to obtain the corresponding oximes and 1-(3-R-1-adamantyl)cthylamines. Dimethyl (3-R-1-adamantylcarbonyl)malonates reacted with phenylhydrazine to give adamantyl-substituted 4,5-dihydropyrazol-5-one derivatives.

Full text of DOI:10.1023/A:1013154831862

Russian Journal of Organic Chemistry, Vol. 37, No. 9, 2001, pp. 1228 1231. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 9, 2001,
pp. 1296 1299.
Original Russian Text Copyright
2001 by Pozdnyakov, Makarova, Moiseev.
Synthesis and Reactivity of 3-R-1-Adamantyl Methyl Ketones
V. V. Pozdnyakov, N. V. Makarova, and I. K. Moiseev
Samara State Technical University, ul. Galaktionovskaya 141, Samara, 443010 Russia
e-mail: moiseev@dp.sstu.samara.ru
Nayanova Samara Municipal University, Samara, Russia
Received December 27, 2000
Abstract A general procedure was proposed for synthesizing 3-R-1-adamantyl methyl ketones from the
corresponding adamantanecarbonyl chlorides and dimethyl malonate in toluene (benzene) in the presence of
sodium hydroxide. Intermediate dimethyl (3-R-1-adamantylcarbonyl)malonates can also be isolated. The
resulting ketones were brought into reactions with hydroxylamine and formamide in the presence of formic
acid to obtain the corresponding oximes and 1-(3-R-1-adamantyl)ethylamines. Dimethyl (3-R-1-adamantyl-
carbonyl)malonates reacted with phenylhydrazine to give adamantyl-substituted 4,5-dihydropyrazol-5-one
derivatives.
We previously reported [1] on the synthesis of
(3-hydroxy-1-adamantyl) methyl ketone by the action
of dimethyl malonate and NaOH on 3-bromo- and
3-chloro-1-adamantanecarbonyl chlorides in toluene
and subsequent hydrolysis. We also succeeded in
isolating intermediate dimethyl (3-bromo- and
3-chloro-1-adamantylcarbonyl)malonates. With the
goal of extending the above procedure to the synthesis
of the other 3-R-1-adamantyl methyl ketones and
revealing the dependence of the reaction direction on
the dissociation constant of 1-adamantanecarboxylic
acids, in the present work we studied the reactions
of 3-chloro-, 3-ethyl-, 3-phenyl-, and 3-amino-1-ada-
mantanecarbonyl chlorides Ia Id and also of 1-ada-
mantylacetyl chloride (Ie) with dimethyl malonate in
toluene (benzene) in the presence of sodium hydroxide
(Scheme 1). As a result, we isolated dimethyl (3-R-1-
adamantylcarbonyl)malonates IIa IId which were
to occur, and the only isolated product was (1-ada-
mantyl)acetic acid. The applicability of sodium
hydroxide for the synthesis of ketones from acyl
chlorides and dialkyl malonates is limited because
of possible hydrolysis of the initial acyl chloride.
Comparison of the dissociation constants of 3-substi-
tuted 1-adamantanecarboxylic acids (pKa 107:
3-Cl-1-AdCOOH, 7.13; 3-Br-1-AdCOOH, 6.46;
3-HO-1-AdCOOH, 4.86; 3-Ph-1-AdCOOH, 1.71) [2]
with those of aliphatic and aromatic acids [pKa 105:
PhCOOH, 6.6; CH3(CH2)5COOH, 1.28; CH3COOH,
1.75] [3] led us to presume that just the difference in
the acidity is the main factor determining different
behavior of acids Ia Id and Ie in the above reaction.
Hydrolysis of ketodiesters IIb IId in a mixture of
acetic acid with water and sulfuric acid (CH3COOH
H2O H2SO4 ratio 10:3:1) afforded the corresponding
3-R-1-adamantyl methyl ketones IIIb IIId. The
hydrolysis of compound IIa in 6 h gave 3-hydroxy-
1-adamantyl methyl ketone (IIIf). By shortening of
1
characterized by IR and H NMR spectroscopy. The
reaction with (1-adamantyl)acetyl chloride failed
Scheme 1.
R = Cl (a), C2H5 (b), C6H5 (c), NH2 (d), OH (f).
1070-4280/01/3709-1228$25.00 2001 MAIK Nauka/Interperiodica

SYNTHESIS AND REACTIVITY OF 3-R-1-ADAMANTYL METHYL KETONES
1229
the hydrolysis time to 1 h we succeeded in isolating
Scheme 3.
66% of 3-chloro-1-adamantyl methyl ketone (IIIa).
In addition, 4% of ketone IIIf was isolated by frac-
tional recrystallization.
Ketones IIIa IIIc and IIIf reacted with hydroxyl-
amine hydrochloride in 50% aqueous alcohol in the
presence of Na2CO3 to give oximes IVa IVc and IVf
in high yields. The reduction of IVa IVc and IVf
with metallic sodium in boiling anhydrous ethanol,
followed by treatment with gaseous hydrogen chloride
afforded 20 29% of amine hydrochlorides Va Vc and
Vf (Scheme 2). The same products (compounds Va,
Vb, and Vf) were obtained in 15 32% yield by direct
reductive amination of ketones IIIa, IIIb, and IIIf
with formamide in the presence of formic acid and
subsequent treatment with gaseous HCl (Scheme 2).
R = H (a), Br (b).
Scheme 2.
UV-254 plates. Tables 1 and 2 contain yields, physical
properties, and spectral parameters of the prepared
adamantyl ketones and their derivatives.
Dimethyl (3-R-1-adamantylcarbonyl)malonates
IIa IId. A mixture of 1.08 g (27 mmol) of sodium
hydroxide, 12 ml of toluene (or benzene), and 2.5 ml
(21.6 mmol) of dimethyl malonate was vigorously
stirred for 30 40 min at 25 C, and a solution of
10.8 mmol of 1-adamantylcarbonyl chloride Ia Id
in 12 ml of toluene (or benzene) was added to the
resulting suspension. The mixture was stirred for 1 h
at room temperature and was poured into 50 ml of
10% sulfuric acid. The organic phase was separated,
washed with 2 50 ml of water, 50 ml of a 10% solu-
tion of sodium carbonate, and again with 2 50 ml of
water, dried, and distilled under reduced pressure.
Dimethyl malonate IIc was a thick oily material
which decomposed on distillation in high vacuum.
Crystalline products IIa, IIb, and IId were recrystal-
lized from alcohol.
3-R-1-Adamantyl methyl ketones IIIa IIId and
IIIf. A mixture of 6.1 mmol of ketodiester II, 20 ml
of acetic acid, 6 ml of water, and 2 ml of concentrated
sulfuric acid was refluxed for 2 4 h. It was then
cooled and poured into ice water. Ketones IIIa and
IIId were filtered off and recrystallized from hexane.
Products IIIb, IIIc, and IIIf were isolated by extrac-
tion with chloroform. Compounds IIIb and IIIc were
purified by vacuum distillation.
We also examined the possibility of using pre-
viously synthesized ketodiesters of the adamantane
series [1] to prepare heterocyclic compounds. For this
purpose, dimethyl (1-adamantylcarbonyl)malonate
(VIa) and dimethyl (3-bromo-1-adamantylcarbonyl)-
malonate (VIb) were treated with phenylhydrazine in
acetic acid at room temperature. The reaction yielded
methyl 3-(3-R-1-adamantyl)-1-phenyl-5-oxo-4,5-di-
hydropyrazole-4-carboxylates VIIa and VIIb, respec-
tively (Scheme 3).
EXPERIMENTAL
1
3-R-1-Adamantyl methyl ketone oximes IVa IVc
and IVf. A solution of 0.77 g (11 mmol) of hydroxyl-
amine hydrochloride and 0.53 g (5 mmol) of sodium
carbonate in 5 ml of water was added to a solution
of 10 mmol of ketone III in 15 ml of ethanol. The
The H NMR spectra were recorded on a Bruker
AC-300 spectrometer (300.13 MHz) in DMSO using
HMDS as internal reference. The IR spectra were
measured on a Specord M-80 instrument in KBr. The
purity of the products was checked by TLC on Silufol
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

1230
POZDNYAKOV et al.
Table 1. Yields, melting points, TLC data, and IR spectra of compounds II V and VII
Comp.
no.
Yield,
%
1
mp,
C
Rf (eluent)
IR spectrum, , cm
IIb
67
60
41
66
51
62
64
84
84
81
60
15
49 51
0.86
2920, 2860 (CH2, Ad); 1750, 1720 (COOCH3, C O)
2920, 2860 (CH2, Ad); 1750, 1720 (COOCH3, C O)
(CCl4 Me2CO, 6: 1)
a
IIc
0.33
(hexane Me2CO, 3: 1)
IId
74 76
0.25
(CCl4)
0.74
3450 (NH2); 2920, 2860 (CH2, Ad); 1765, 1720 (COOCH3,
C O)
2920, 2860 (CH2, Ad); 1710 (C O)
IIIa
IIIb
IIIc
IIId
IVa
IVb
IVc
IVf
Va
53 55
(CCl4 Me2CO, 6: 1)
b
0.60
(CCl4)
0.42
(CCl4)
2920, 2860 (CH2, Ad); 1720 (C O)
c
2920, 2860 (CH2, Ad); 1720 (C O)
101 103
154 156
0.55
(CCl4 Me2CO, 6: 1)
0.53
(CCl4 Me2CO, 6: 1)
0.91
(CCl4 Me2CO, 6: 1)
0.48
(CCl4)
0.20
(CCl4 Me2CO, 2: 1)
3450 (NH2); 2920, 2860 (CH2, Ad); 1710 (C O)
3250 (OH); 2910, 2860 (CH2, Ad); 1665 (C N)
3260 (OH); 2920, 2850 (CH2, Ad); 1660 (C N)
3220 (OH); 2920, 2860 (CH2, Ad); 1670 (C N)
3300 (OH); 2900, 2850 (CH2, Ad); 1620 (C N)
3000 (NH+3); 2910, 2860 (CH2, Ad)
133 134
148 149.5
179.5 181.5
296 297
(decomp.)
233 235
242 244
300 301
(decomp.)
128 130
Vb
Vc
Vf
20
21
32
3020 (NH+3); 2920, 2860 (CH2, Ad)
3000 (NH+3); 2920, 2860 (CH2, Ad)
3280 (OH); 3000 (NH+3); 2920, 2860 (CH2, Ad)
VIIa
VIIb
82
51
0.48
(CCl4 Me2CO, 2: 1)
0.76
2910, 2860 (CH2, Ad); 1765, 1750 (COOCH3, C O); 1650
(C N)
65 67
2900, 2850 (CH2, Ad), 1730, 1720 (COOCH3, C O); 1620
(C N)
(Me2CO)
a
b
c
Decomposes on attempted distillation.
bp 101 109 C (2 mm); n2D0 1.4996.
bp 112 119 C (2 mm); n2D5 1.5606.
mixture was stirred for 1 h, and the precipitate was
filtered off and recrystallized from alcohol.
chloride. The precipitate was filtered off, washed with
anhydrous acetone, and recrystallized from ethanol.
1-(3-R-1-Adamantyl)ethylamine hydrochlorides
Va Vc and Vf. a. A mixture of 10 mmol of ketone
III, 2 ml (50 mmol) of formamide, and 4 ml
(100 mmol) of formic acid was refluxed for 3 h. It
was then cooled, 20 ml of 20% hydrochloric acid was
added, and the mixture was refluxed for 2 h, cooled,
and made alkaline (pH 11 12). The products were
extracted into diethyl ether, the extract was dried over
potassium carbonate and saturated with hydrogen
b. A solution of 2.2 mmol of oxime IV in 25 ml
of anhydrous alcohol was heated to the boiling point,
2.6 g (11.3 mmol) of metallic sodium was slowly
added through the reflux condenser, and the mixture
was heated until it became homogeneous. Water,
25 ml, was added, the solvent was distilled off under
reduced pressure, and the residue was extracted with
ether. The extract was dried over potassium hydroxide
and saturated with hydrogen chloride. The precipitate
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

SYNTHESIS AND REACTIVITY OF 3-R-1-ADAMANTYL METHYL KETONES
1231
Table 2. 1H NMR spectra ( , ppm) of compounds II V and VII
Comp.
no.
CH2, CH (Ad)
Other protons
IIb
IIc
IId
1.40 2.05 m (14H) 0.78 t (3H, CH2CH3), 1.12 q (2H, CH2CH3), 3.68 s (6H, 2CH3OOC), 5.48 s (1H, CH)
1.85 2.06 m (14H) 3.65 s (6H, 2CH3OOC), 5.24 s (1H, CH), 7.17 7.30 m (5H, C6H5)
1.65 2.06 m (14H) 3.15 br.s (2H, NH2), 3.66 s (6H, 2CH3OOC), 5.22 s (1H, CH)
1.65 2.02 m (14H) 2.17 s (3H, CH3CO)
1.38 1.95 m (14H) 0.75 t (3H, CH2CH3), 1.07 q (2H, CH2CH3), 2.10 s (3H, CH3CO)
1.80 2.02 m (14H) 2.15 s (3H, CH3CO), 7.20 7.30 m (5H, C6H5)
IIIa
IIIb
IIIc
IIId
IVa
IVb
IVc
IVf
Va
1.64 2.02 m (14H) 2.16 s (3H, CH3CO), 3.24 br.s (2H, NH2)
1.65 2.01 m (14H) 2.15 s (3H, CH3CO), 9.50 s (1H, NOH)
1.37 1.95 m (14H) 0.79 t (3H, CH2CH3), 1.09 q (2H, CH2CH3), 2.10 s (3H, CH3CO), 9.30 s (1H, NOH)
1.73 2.00 m (14H) 2.11 s (3H, CH3), 7.15 7.30 m (5H, C6H5), 9.38 s (1H, NOH)
1.53 1.68 m (14H) 2.12 s (3H, CH3CO), 4.38 s (1H, OH), 12.50 s (1H, NOH)
1.50 2.05 m (14H) 1.18 d (3H, CH3), 2.84 m (1H, CH), 8.05 br.s (2H, NH2)
1.65 2.10 m (14H) 0.80 t (3H, CH2CH3), 1.15 d (3H, CH3), 1.35 q (2H, CH2CH3), 2.95 m (1H, CH),
8.3 br.s (2H, NH2)
Vb
Vc
VIIa
VIIb
1.50 2.10 m (14H) 1.40 d (3H, CH3), 2.80 m (1H, CH), 4.35 s (1H, OH), 8.12 br.s (2H, NH2)
1.65 2.00 m (15H) 2.25 s (3H, CH3OOC), 4.85 s (1H, CH, pyrazole), 6.80 7.50 m (5H, C6H5)
1.60 1.95 m (14H) 2.15 s (3H, CH3OOC), 4.62 s (1H, CH, pyrazole), 6.75 7.40 m (5H, C6H5)
was filtered off, washed with anhydrous acetone,
dried, and recrystallized from ethanol.
REFERENCES
1. Makarova, N.V., Moiseev, I.K., and Zemtsova, M.N.,
Russ. J. Gen. Chem., 1999, vol. 69, no. 4, pp. 675
676.
Methyl 3-(3-R-1-adamantyl)-5-oxo-1-phenyl-
4,5-dihydropyrazole-4-carboxylates VIIa and VIIb.
A mixture of 1.7 mmol of ketodiester VIa or VIb,
1.7 mmol of phenylhydrazine, and 5 ml of glacial
acetic acid was stirred for 54 h at room temperature.
The precipitate of compound VIIa or VIIb was fil-
tered off and recrystallized from alcohol.
2. Stetter, H. and Mayer, J., Chem. Ber., 1962, vol. 95,
no. 3, pp. 667 672.
3. Spravochnik khimika (Chemist’s Handbook), Moscow:
Khimiya, 1964, vol. 3, p. 85.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001