Syntheses of heterocycles from the sodium salts of 3-(1-adamantyl)-1-hydroxy-1-propen-3-one and 4-(1-adamantyl)-1-hydroxy-1-buten-3-one

Article abstract of DOI:10.1023/A:1012443306632

The interaction of the sodium salts of 3-(1-adamantyl)-l-hydroxy-l-propen-3-one and 4-(1-adamantyl)- 1-hydroxy-l-buten-3-one with hydroxylamine, hydrazine, and guanidine leads to the synthesis of 5-(1-adamantyl)-5-hydroxy- and 5-(1-adamantylmethyl)-5- hydroxy-Δ²_isoxazolines, 3-(1-adamantyl)-and 3-(1-adamantylmethyl)pyrazoles, 3-(1-adamantyl)-2-phenylpyrazole, and 4-(1-adamantyl)-2-amino- and 4-(1-adamantylmethyl)-2-aminopyrimidines.

Full text of DOI:10.1023/A:1012443306632

Chemistry of Heterocyclic Compounds, Vol. 37, No. 7, 2001
SYNTHESES OF HETEROCYCLES
FROM THE SODIUM SALTS OF
3-(1-ADAMANTYL)-1-HYDROXY-
1-PROPEN-3-ONE AND 4-(1-ADAMANTYL)-
1-HYDROXY-1-BUTEN-3-ONE
N. V. Makarova, M. N. Zemtsova, and I. K. Moiseev
The interaction of the sodium salts of 3-(1-adamantyl)-1-hydroxy-1-propen-3-one and 4-(1-adamantyl)-
1
5
-hydroxy-1-buten-3-one with hydroxylamine, hydrazine, and guanidine leads to the synthesis of
2
-(1-adamantyl)-5-hydroxy- and 5-(1-adamantylmethyl)-5-hydroxy-Δ -isoxazolines, 3-(1-adamantyl)-
and 3-(1-adamantylmethyl)pyrazoles, 3-(1-adamantyl)-2-phenylpyrazole, and 4-(1-adamantyl)-2-
amino- and 4-(1-adamantylmethyl)-2-aminopyrimidines.
2
(
1-adamantyl)acetone, 2-aminopyrimidines, 5-hydroxy-Δ -isoxazolines, 3-(1-adamantyl)-1-
Keywords:
hydroxy-1-propen-3-one sodium salt, 4-(1-adamantyl)-1-hydroxy-1-buten-3-one sodium salt, pyrazoles,
cyclization.
Scores of heterocyclic compounds from simple four-membered rings to the most complex condensed
heterocyclic systems have been obtained from β-chloro- and β-aminovinyl ketones. The sodium salts of
3
-R-1-hydroxy-1-propen-3-ones are infrequently used in syntheses of heterocycles [1-3]. For example, syntheses
of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines [1], furans [2], and 2-pyridones [3] have been described.
The sodium salt of 3-(1-adamantyl)-1-hydroxy-1-propen-3-one (1) has been used successfully in the
synthesis of 6-(1-adamantyl)-3-cyano-2(1H)-pyridinones, thiones, and selenones [4-8]. This reaction has also
been extended to aromatic [9] and unsaturated [10] compounds. The sodium salt 1 was obtained by the
interaction of methyl (1-adamantyl) ketone with ethyl formate and sodium in ether [5,6].
Based on this reaction we have synthesized the sodium salt of 4-(1-adamantyl)-1-hydroxy-1-buten-3-one
(
3) from (1-adamantyl)acetone (2). Compound 3 is unstable, decomposing in the air in a few days and has a high
melting point.
O
O
Na
CH CMe + HCOOEt
CH CCH=CHONa
2
2
2
3
In a continuation of studies on the synthesis of adamantane-containing heterocycles [11,12], the reaction
of sodium salts 1 and 3 with the hydrochlorides of hydroxylamine, hydrazine, and phenylhydrazine, and
guanidine nitrate by boiling in 50% aqueous ethanol gave 5-(1-adamantyl)-5-hydroxy- (4a) and
_
_________________________________________________________________________________________
Samara State Technical University, Samara 443100, Russia. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 912-915, July, 2001. Original article submitted August 2, 1999.
840
0009-3122/01/3707-0840$25.00©2001 Plenum Publishing Corporation

2
5
-(1-adamantylmethyl)-5-hydroxy-Δ -isoxazolines (4b), 5-(1-adamantyl)- (5a) and 5-(1-adamantylmethyl)-
pyrazoles (5b), 5-(1-adamantyl)-1-phenylpyrazole (5c), and 4-(1-adamantyl)-2-amino- (6a) and
-(1-adamantylmethyl)-2-aminopyrimidines (6b).
4
OH
(CH2) n
(CH2)n
O
N
N
N
4
4
a n = 0
b n = 1
6a n = 0
6b n = 1
NH2
NH OH.HCl
.
NH CNH HNO
2 2 3
2
NH
O
(
CH ) CCH=CHONa
2 n
1
, 3
.
.
NH NHPh HCl
2
NH NH HCl
2
2
(
CH2)n
N
Ph
c n = 0
N
N
H
N
NH NHPh
2
5
O
5
5
a n = 0
b n = 1
CCH=CH
N
7
In addition, pyrazole 5c was obtained from 3-(1-adamantyl)-1-piperidino-1-propen-3-one (7) and
phenylhydrazine by boiling in acetic acid. The β-aminovinyl ketone 7 was obtained by the reaction of salt 1
with piperidine hydrochloride. The physicochemical characteristics of the synthesized compounds and data of
1
their IR and H NMR spectra are given in Tables 1 and 2.
TABLE 1. Physicochemical Characteristics of the Synthesized Heterocycles
Found, %
Com-
Empirical
——————
Calculated, %
mp, °С
R
f
*
Yield, %
pound formula
С
Н
N
4
4
5
5
5
6
6
a
b
a
b
c
C
C
C
C
C
C
C
13
14
13
14
19
14
15
H
H
H
H
H
H
H
19NO
2
2
70.61
8.65
8.65
6.30
6.33
160-162
88-89
0.79a
0.48a
0.86b
0.37a
0.54c
0.70b
0.74a
41
42
77
72
59
50
70
7
0.56
21NO
71.50
9.00
6.00
7
1.46
8.99
5.95
18
20
22
19
21
N
2
N
2
N
2
N
3
N
3
77.13
9.00
8.97
13.80
13.85
128-129
184-186
130-132
45-47
7
7.18
77.60
7.73
9.21
12.93
7
9.32
12.95
82.00
7.91
7.97
10.16
10.06
8
1.97
a
b
73.35
8.40
18.25
7
3.32
8.35
18.32
74.00
8.68
8.70
17.20
17.27
190-192
7
4.03
_
*
______
Eluent acetone–CCl
4
: a) 1:4; b) 1:2; c) 1:6.
8
41

1
TABLE 2. IR and H NMR Spectra of the Synthesized Heterocycles
IR spectra, ν, cm-1
С=N CH2 Ad OH
1H NMR, δ, ppm
Com-
pound
NH/ 6СН2 Ad 3CHAd AdCH
2
H
Het
other protons
NH
2
(12Н) (3Н)
(2Н)
4
4
5
5
5
6
a
b
a
b
c
1620 2850, 3330
900
1640 2850, 3400
900
1610 2850,
900
1600 2850,
900
1610 2850,
900
1640 2850,
900
—
—
1.70, d 2.00, s
—
3.45 (2Н, d, СН
2
),
10.10
2
8.25 (1Н, t, C=N)
(1Н, s, ОН)
1.65, d 1.95, s 2.50, s 3.30 (2Н, d, СН
2
),
11.20
2
8.40 (1Н, t, C=N)
(1Н, s, ОН)
—
—
—
—
3000 1.70, d 1.95, s
—
5.90 (1Н, d, Н-4),
14.45
2
7.30 (1Н, d, Н-5)
(1Н, s, NH)
3100 1.70, d 1.95, s 2.45, s 5.90 (1Н, d, Н-4),
7.30 (1Н, d, Н-5)
—
14.45
2
(1Н, s, NH)
2
a
3300 1.70, d 1.90, s
—
6.42
6.05
2
(1Н, d, Н-5pyrimidine), (2Н, br. s,
8
.08
NH )
2
(
1Н, d, Н-6pyrimidine)
6
b
1580 2850,
900
—
3320 1.70, d 1.95, s 2.40, s 6.42
6.05
NH
2
(1Н, d, Н-5pyrimidine), (2Н,br. s,
8
.08
2
)
(
1Н, d, Н-6pyrimidine)
The reaction of the sodium salts of compounds 1 and 3 with hydroxylamine, hydrazine, and guanidine
3
has therefore led to the synthesis of 5-(1-adamantyl)-5-hydroxy- and 5-(1-adamantylmethyl)-5-hydroxy-Δ -
isoxazolines, 3-(1-adamantyl)- and 3-(1-adamantylmethyl)pyrazoles, 3-(1-adamantyl)-2-phenylpyrazoles, and
4
-(1-adamantyl)-2-amino- and 4-(1-adamantylmethyl)-2-aminopyrimidines. In the proposed procedure the use of
readily oxidizable bases of nitrogen-containing compounds has been avoided which enables the desired
compounds to be obtained in high yield.
EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker AC 300 (300.13 MHz) in DMSO-d
6
, internal standard was
HMDS. The IR spectra were taken on a Specord M 80 instrument in KBr disks. The purity of compounds was
checked by TLC (Silufol UV 254, visualization in iodine vapor).
General Procedure for the Synthesis of Heterocycles (4-6). A solution of sodium salt 1 or 3
(
2.2 mmol) and hydroxylamine hydrochloride (hydrazine hydrochloride, guanidine nitrate) (2.2 mmol) in 50%
ethyl alcohol (10 ml) was boiled for 4-15 h until precipitation of the desired heterocycle. The solid was filtered
off and recrystallized from alcohol.
3
-(1-Adamantyl)-1-piperidino-1-propen-3-one (7). A solution of the sodium salt 1 and piperidine
hydrochloride (0.27 g, 2.2 mmol) in 50% ethyl alcohol (10 ml) was boiled for 12 h. The precipitated solid was
filtered off and recrystallized from alcohol. Yield 91%; mp 168-170°C, R 0.31 (acetonitrile). IR spectrum,
adamant.), 1660 (C=O). H NMR spectrum, δ, ppm: 1.25 (2H, m, p-H piperidyl);
f
-1
1
ν, cm : 2860 and 2910 (CH
2
1
.55 (4H, m, m-H piperidyl); 1.70 (12H, d, CH adamant.); 1.95 (3H, s, CH adamant.); 2.30 (4H, m,
2
o-H piperidyl); 4.95 (1H, d, CHN); 7.25 (1H, d, CHCO). Found, %: C 78.86; H 9.64; N 5.23. C18H27NO.
Calculated, %: C 79.07; H 9.95; N 5.12.
3
-(1-Adamantyl)-2-phenylpyrazole (5c). A solution of β-aminovinyl ketone 7 (0.5 g, 1.8 mmol) and
phenylhydrazine (0.27 ml, 2.7 mmol) in glacial acetic acid (10 ml) was boiled for 8 h. The reaction mixture was
poured onto ice, the solid was filtered off, and recrystallized from alcohol.
8
42

REFERENCES
1
2
3
4
5
6
.
.
.
.
.
.
R. N. Schut, Chem. and Ind., 1246 (1960).
M. Valenta, Coll. Czech. Chem. Commun., 32, 897 (1967).
P. Nantka-Namirski and L. Kaszmarek, Acta Pol. Pharm., 34, 133 (1977).
V. P. Litvinov, E. E. Apenova, and Yu. A. Sharanin, Izv. Akad. Nauk SSSR, Ser. Khim., 2408 (1984).
V. P. Litvinov, E. E. Apenova, and Yu. A. Sharanin, Izv. Akad. Nauk SSSR, Ser. Khim., 145 (1986).
E. E. Apenova, Yu. A. Sharanin, B. M. Zolotarev, and V. P. Litvinov, Izv. Akad. Nauk SSSR, Ser. Khim.,
4
06 (1986).
7.
8.
9.
V. P. Litvinov, E. E. Apenova, and Yu. A. Sharanin, Izv. Akad. Nauk SSSR, Ser. Khim., 386 (1987).
V. Yu. Mortikov, V. P. Litvinov, and A. M. Shestopalov, Khim.-farm. Zh., No. 5, 41 (1991).
L. A. Rodinovskaya, V. K. Promonenkov, and Yu. A. Sharanin, Zh. Org. Khim., 21, 1578 (1985).
N. G. Frolova, V. K. Zav'yalova, and V. P. Litvinov, Zh. Org. Khim., 33, 291 (1997).
1
1
1
0.
1.
2.
N. V. Makarova, M. N. Zemtsova, and I. K. Moiseev, Khim. Geterotsikl. Soedin., 1580 (1993).
N. V. Makarova, M. N. Zemtsova, and I. K. Moiseev, Khim. Geterotsikl. Soedin., 130 (1995).
843