Transformations of sym-octahydroxanthene-1,8-diones and 1,8-dioxo-sym-octahydroxanthylium salts in recyclization under the influence of amines

Article abstract of DOI:10.1007/s10593-006-0042-1

The chemical behavior of 9-R-sym-octahydroxanthene-1,8-diones and salts based on them in recyclization reactions under the influence of amines was studied. The effect of the basicity of the amines on the direction of recyclization was established. A metho

Full text of DOI:10.1007/s10593-006-0042-1

Chemistry of Heterocyclic Compounds, Vol. 42, No. 1, 2006
TRANSFORMATIONS OF sym-OCTAHYDRO-
XANTHENE-1,8-DIONES AND 1,8-DIOXO-sym-
OCTAHYDROXANTHYLIUM SALTS IN RECYCLIZATION
UNDER THE INFLUENCE OF AMINES
1
2
Yu. M. Shchekotikhin and T. G. Nikolaeva
The chemical behavior of 9-R-sym-octahydroxanthene-1,8-diones and salts based on them in
recyclization reactions under the influence of amines was studied. The effect of the basicity of the amines
on the direction of recyclization was established. A method is proposed for the single-stage synthesis of
sym-octahydroacridine-1.8-dione oximes based on 1,8-dioxo-sym-octahydroxanthenes. Conditions were
worked out for the oxidation of sym-octahydroxanthene-1,8-diones and N-R-decahydroacridinediones to
the corresponding salts.
Keywords: decahydroacridine-1,8-diones, sym-octahydroacridine-1,8-dione oximes, 1,8-dioxo-sym-
octahydroacridinium perchlorates, sym-octahydroxanthene-1,8-diones, 1,8-dioxo-sym-octahydro-
xanthylium salts, amination, oxidation, recyclization.
9
-R-1,8-Dioxo-sym-octahydroxanthenes are well known and are easily formed when α-R-methylene-bis-
2
,2'-cyclohexane-1,3-diones are heated in acidic media [1, 2]. However, in spite of the presence of several
reaction centers, their chemical transformations have been studied relatively little. There are isolated examples of
the recyclization of 1,8-dioxo-sym-octahydroxanthenes to decahydroacridine-1,8-diones unsubstituted at the
nitrogen atom during the action of ammonia in alcohol at 110-130°C [3, 4], ammonium acetate with boiling in an
alcohol–acetic acid medium [5, 7], and urea with heating at 120°C in DMSO [8].
In order to establish the possibility of synthesizing decahydroacridine-1,8-diones with various structures
from 1,8-dioxo-sym-octahydroxanthenes we studied the chemical behavior of the latter during recyclization in
the presence of amines with various basicities (ammonia, benzylamine, aniline with heat in formic acid, or
hydroxylamine hydrochloride boiled in solution in isopropyl alcohol).
The reaction of the octahydroxanthenes 1a-d with formamide in formic acid was conducted at 100°C.
Under these conditions the ammonia formed as a result of decarbonylation of the formamide reacts with the
initial compounds 1a-d with the formation of decahydroacridine-1,8-diones 2a-d with yields of 71-82%. The
process takes place smoothly in 4-6 h.
When benzylamine was used in the reaction 3-(benzylamino)-5,5-dimethyl-2-cyclohexen-1-one (3)
(
yields 28-42%) and N-benzylformamide were isolated as final products.
Octahydroxanthene-1,8-diones 1a-d do not enter into reaction with aniline even after prolonged boiling
10-12 h) in formic acid. This agrees well with data in [6], where analogous reactions were carried out with
(
aromatic amines in acetic acid.
_
_________________________________________________________________________________________
1
2
ZAO Nita-Farm, Saratov 410005, Russia; e-mail: pto@nita-farm.ru. N. G. Chernyshevsky Saratov
State University, Saratov 410026, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1,
pp. 32-38, January, 2006. Original article submitted July 9, 2002.
2
8
0009-3122/06/4201-0028©2006 Springer Science+Business Media, Inc.

As a result of the recyclization of 1,8-dioxo-sym-octahydroxanthenes 1a-c by the action of
hydroxylamine hydrochloride in isopropyl alcohol the dioximes of sym-octahydroacridine-1,8-diones 4a-c were
isolated with yields of 79-82%. The process probably takes place through the formation of the corresponding
decahydroacridinediones, the subsequent oxidation and oximation of which lead to the octahydro derivatives
4
a-c [9].
O
R
O
HCONH2
HCOOH
Me
Me
Me
Me
N
H
O
2a–d
PhCH NH2
2
Me
Me
HCOOH
O
R
O
NH
R
CH Ph
2
3
Me
Me
O
O
Me
Me
O
PhNH
HCOOH
2
Me
Me
Me
Me
1
a–d
N
Ph
HO
N
R
N
OH
.
NH OH HCl
2
Me
Me
Me
Me
i-PrOH
N
4
a–c
1
6 4
, 2, 4 a R = H, b R = Me, c R = Ph; 1, 2 d R = 4-MeOC H
The obtained results and the data from [3-8] make it possible to conclude that the nature of the reaction
medium (ethyl alcohol, isopropyl alcohol, acetic acid, formic acid, alcohol–acid medium, DMSO) does not affect
the direction of recyclization and that the determining factor is the basicity of the amines. The transformation of
the 1,8-dioxo-sym-octahydroxanthenes into hydroacridine-1,8-diones only takes place smoothly under the
influence of ammonia and amines whose basicity is comparable with the basicity of ammonia and
hydroxylamine. Weakly basic aromatic amines do not enter into reaction with 1,8-dioxo-sym-
octahydroxanthenes at all, while strong bases such as benzylamine promote their destructive cleavage with the
formation of 3-N-R-5,5-dimethylcyclohex-2-enones.
In contrast to the sym-octahydroxanthene-1,8-diones, the recyclization of their salts in the presence of
amines should take place in a more well-defined manner.
Since the oxidation of sym-octahydroxanthene-1,8-diones to the respective salts had not been realized
before, we proposed a method for the production of the latter by the oxidation of compounds 1a-c with acetic
anhydride in the presence of perchloric acid. The 1,8-dioxo-sym-octahydroxanthylium perchlorates 5a-c were
isolated with yields of 48-64% by boiling the initial reagents for 6-8 h.
2
9

O
R
O
Ac O
2
Me
Me
1
a–c
Me
Me
+
HClO4
O
–
ClO4
5
a–c
1
R NH2
i-PrOH
O
R
O
O
R
O
Ac O
2
Me
Me
Me
Me
Me
Me
Me
Me
+
HClO4
N
N
R
–
R1
ClO4
1
7a–d
6a–d
5
a R = H, b R = Me, c R = Ph; 6, 7 a,b R = H, c R = Me, d R = 4-MeOC H ,
6 4
1
1
a,c,d R = Me, b R = Ph
It was established that heating of the salts 5a,b (7 h) in isopropyl alcohol, saturated with a fivefold molar
excess of methylamine or containing an equimolar amount of aniline, leads irrespective of the basicity of the
1
amine to their recyclization to the N-R -1,8-dioxo-sym-octahydroacridinium perchlorates 6a-c, which were
isolated with yields of 32-87%.
In the literature the synthesis of 1,8-dioxo-sym-octahydroacridinium salts is represented by a single
publication [10], in which the oxidation of N-aryldecahydroacridine-1,8-diones unsubstituted at position 9 with
nitrobenzene in the presence of perchloric acid was used for their production. The reaction was carried out at
1
30°C for 28 h, and the yields of the respective salts did not exceed 6-26%. For comparison we realized the
1
oxidation of 9-R-N-R -decahydroacridine-1,8-diones 7a-d under the conditions used for the synthesis of the
,8-dioxo-sym-octahydroxanthylium salts. It was shown that the method can be used successfully not only for
1
the oxidation of a pyran ring but also a 1,4-dihydropyridine ring. The transformation of the compounds 7a-d into
the salts 6a-d takes 6-8 h, and the yields of the latter amount to 63-71%.
1
The structure of all the synthesized substances was established on the basis of data from IR and H NMR
spectroscopy and also, for the known compounds 2a-d, 3, 4a,c, and 6b, by comparison of their melting points
with published data.
The IR spectra of the decahydroacridinediones 2a-d are characterized by the presence of two strong
-
1
absorption bands in the regions of 1585-1620 and 1640-1660 cm , corresponding to the stretching vibrations of
the conjugated system of bonds C=C–C=O. In the spectra of these compounds the enamine NH group is
-
1
characterized by absorption at 3250-3300 cm . The spectra of the dioximes 4a-c contain a strong broad
-
1
absorption band in the region of 3150-3400 cm , confirming the presence of an associated hydroxyl group. In
-
1
the spectra of the salts 5 and 6 the stretching vibrations of the carbonyl group appear at 1700-1720 cm , and the
-
-1
vibrations of the ClO ion at 1090-1110 cm .
4
1
The H NMR spectra of the decahydroacridinediones 2a-d, the dioximes 4a-c, and the salts 5a-c and
6
a-d correspond fully to their structure (Table 1).
The most characteristic for compounds 2a-d are the signals for the proton of the amino group, which
appear in the form of a broad singlet in the region of 8.12-9.09 ppm, and the chemical shifts of the hydrogen
atoms at position 9, which appear at 3.24 (compound 2a) or 4.12-5.24 ppm. For the dioxime 4a and the salts
6
a,b the signal of the proton at the C atom is shifted downfield – 7.63-9.83 ppm. In the spectra of the dioximes
(9)
the chemical shifts of the protons of the hydroxyl groups are in the region of 11.54-11.64 ppm.
3
0

1
TABLE 1. The H NMR Spectra of Decahydroacridine-1,8-diones 2a-d,
Octahydroacridine-1,8-dione Oximes 4a-c, and Salts 5a-c and 6a-d
Chemical shifts, δ, ppm (SSCC, J, Hz)
Com-
pound
H
2
-2,2,
2
Н -4,4,
-5,5, 4Н, s
H
2
-9,9 /H-9 С(CH
3
)
2
, s
other signals
Н
2
-7,7, s
H
2
2
2
2
2
a
b
c
2.32 (4Н)
2.35 (4H)
2.32 (2H),
2.18
3.24
2H, s)
1.06 (12Н)
9.09 (1Н, br. s, NН)
(
2.23
2.20
2.24
4.12
1H, m)
1.02 (6Н),
1.06 (6Н)
0.88 (3Н, d, J = 6.4, 9-CH
8.12 (1Н, br. s, NН)
3
);
(
5.24
(1H, s)
0.98 (6H),
1.08 (6H)
7.18-7.26 (5H, m, HPh);
8.24 (1H, br. s, NH)
2
.40 (2H)
2.36 (2H),
.44 (2H)
d
5.12
(1H, s)
1.00 (6H),
1.10 (6H)
3.72 (3H, s, OCH
3
);
2
6.78 (2H, d, J = 8.5, HAr-2',6');
7
8
.22 (2H, d, J = 8.5, HAr-3',5');
.18 (1Н, br. s, NН)
4
4
4
a
b
c
2.38 (2Н)
2.40 (2Н)
2.42 (2Н)
2.24
2.26
2.26
7.63
1Н, s)
1.12 (12Н)
1.12 (12Н)
1.06 (6Н),
11.58 (2Н, br. s, ОН)
(
—
1.06 (3Н, s, 9-CH
3
);
1
1.64 (2Н, br. s, ОН)
—
7.28-7.63 (5H, m, HPh);
1
.12 (6Н)
11.54 (2H, br. s, ОH)
5
5
5
a
b
c
2.94 (2H)
2.91 (2H)
2.99 (2H)
2.77
2.80
2.81
9.83
—
1.20 (12H)
1.19 (12H)
1.09 (6H),
–
1.16 (3Н, s, 9-CH
3
)
—
7.41-7.72 (5H, m, HPh
)
)
1
.18 (6H)
6
6
6
6
a
b
c
2.92 (2Н)
2.90 (2Н)
3.02 (2Н)
2.98 (2Н)
2.80
2.76
2.74
2.76
9.73
1Н, s)
1.20 (12Н)
1.20 (12Н)
1.16 (12Н)
1.08 (6Н),
4.12 (3Н, s, NCH
7.63-7.72 (5H, m, HPh
1.12 (3Н, s, 9-CH );
3
)
(
9.74
1Н, s)
(
—
3
3
.66 (3Н, s, NCH
3
)
d
—
3.58 (3Н, s, NCH
4.01 (3Н, s, OCH
3
);
);
1
.18 (6Н)
3
7
7
.08 (2H, d, J = 8.6, HAr-2',6');
.56 (2H, d, J = 8.6, HAr-3',5')
TABLE 2. The Characteristics of the Synthesized Compounds
Found, %
Com-
pound
Empirical
formula
——————
Calculated, %
mp, °С
Yield, %
С
Н
N
4
5
5
5
6
6
6
6
b
a
b
c
C
C
C
C
C
C
C
C
18
17
18
23
18
23
19
25
H
H
H
H
H
H
H
H
25
N
3
O
2
68.74
7.99
7.94
7.00
7.13
7.52
7.39
5.89
5.57
6.35
6.23
5.99
5.85
6.92
6.51
6.41
6.10
13.21
13.33
267-269
217-219
189-191
201-202
235-237
283-285
182-184
236-237
80
48
6
8.57
27ClO
29ClO
25ClO
7
54.27
3.90
—
—
—
5
7
7
54.83
5.03
53
5
61.17
1.54
64
6
a
b
c
24СlNO
26ClNO
26ClNO
30ClNO
6
6
6
7
56.49
6.03
3.91
3.63
3.42
3.13
3.31
3.50
3.13
2.85
48 (67*)
32 (71*)
87 (63*)
65*
5
61.79
1.68
6
57.38
7.07
5
d
60.85
1.04
6
_
*
______
The yields of the products obtained from compounds 7a-d.
3
1

Thus, by studying the transformations of 9-R-sym-octahydroxanthene-1,8-diones in amination and
oxidation reactions it was possible to develop conditions for the production of decahydroacridine-1,8-diones,
1
9
-R-sym-octahydroacridinedione dioximes, and 9-R-1,8-dioxooctahydroxanthylium and 9-R-10-R -1,8-dioxo-
sym-octahydroacridinium salts from them.
EXPERIMENTAL
The IR spectra were recorded on a Specord M-80 instrument (suspensions in vaseline oil and
1
hexachlorobutadiene). The H NMR spectra were obtained on a Bruker AC-300 spectrometer (300 Hz) in
deuterochloroform (compounds 2a-d), DMSO-d (compounds 4a-c), and CF COOD (compounds 5a-c and 6a-d)
6
3
with TMS as internal standard.
The reactions and the individuality of the compounds were monitored by TLC on Silufol UV-254 plates
with 3:1:1 hexane–acetone–chloroform as eluant and iodine vapor as developer.
The 1,8-dioxo-sym-octahydroxanthenes 1a-d were synthesized by familiar methods [1, 12], and the
decahydroacridine-1,8-diones 7a-d were obtained by the method in [9].
3
,3,6,6-Tetramethyl-9-phenyl-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-dione (2c). A mixture of
the xanthenedione 1c (7.00 g, 20 mmol), formamide (2.70 g, 60 mmol), and formic acid (15 ml) was boiled with
a reflux condenser for 6 h and was then poured into cold water (300 ml). After 12 h the precipitate was filtered
off, washed with water, and recrystallized from isopropyl alcohol.
Decahydroacridinediones 2a,b,d. These compounds were obtained similarly.
3
-(Benzylamino)-5,5-dimethylcyclohexen-2-one (3). A mixture of the xanthenedione 1c (7.00 g,
0 mmol), benzylamine (2.14 g, 20 mmol), and formic acid (15 ml) was boiled with a reflux condenser for 6 h. It
was then cooled, made alkaline with a 1M solution of potassium hydroxide to pH 6, and extracted with ether (3
40 ml). The extract containing N-benzylformamide was separated. The aqueous layer was made alkaline with a
M solution of potassium hydroxide to pH 8 and evaporated. The dry residue was dissolved in 10 ml of
2
×
1
anhydrous acetone and filtered, and 40 ml of ether was added. The precipitate was separated, washed with ether,
and dried. We obtained 3.48 g (38%) of the enamino ketone 3; mp 128-130°C (ethanol) (mp 128-130°C [13]).
1
H NMR spectrum, δ, ppm, (J, Hz): 9.24 (1H, br. s, NH); 7.22 (5H, m, HPh); 5.12 (1H, s, CH); 4.42 (4H, d,
J = 6.2, N–CH ); 2.26 (2H, s, CH ); 2.13 (2H, s, CH ); 0.98 (6H, s, 2CH ).
2
2
2
3
The enamino ketone 3 is formed similarly from the xanthenediones 1a,b,d with yields of 28, 36, and
2% respectively.
,3,6,6-Tetramethyl-9-phenyl-1,2,3,4,5,6,7,8-octahydroacridine-1,8-dione Dioxime (4a). A mixture
of the xanthenedione 1c (7.00 g, 20 mmol), hydroxylamine hydrochloride (5.56 g, 80 mmol), and 2-propanol
50 ml) was boiled with a reflux condenser for 6 h. It was then cooled and poured into cold water (300 ml). After
4
3
(
1
2 h the precipitate that formed was filtered off, washed with water, and recrystallized from ethanol.
Dioximes 4a,b. These compounds were obtained similarly from the xanthenediones 1a,b.
Compounds 2a-d and 4a,c. 2a, yield 71%; mp 300-302°C (mp 301-303°C [11]); 2b, yield 78%;
mp 255-257°C (mp 256-258°C [14]); 2c, yield 82; mp 289-291°C (mp 290-291°C [11]); 2d, yield 79%;
mp 271-273°C (mp 270-272°C [15]); 4a, yield 79%; mp 279-280°C (mp 280°C [11]); 4c, yield 82%;
mp 249-250°C (mp 250°C [16]). Compound 6b, yield 6-25% (mp 284-285°C [10]).
1
,8-Dioxo-3,3,6,6-tetramethyl-9-phenyl-1,2,3,4,5,6,7,8-octahydroxanthylium Perchlorate (5c). A
mixture of xanthenedione 1c (7.00 g, 20 mmol), acetic anhydride (30 ml), and perchloric acid (calculated on
00% HClO ) (20 mmol) was boiled with a reflux condenser for 6 h. It was then cooled, and absolute ether
1
4
(
200 ml) was added. The oily precipitate was separated, isopropyl alcohol (20 ml) was added, and the mixture
was heated to boiling and cooled. After 4 h the crystals that separated were filtered off, washed with isopropyl
alcohol, and dried. The product was recrystallized from isopropyl alcohol.
Perchlorates 5a,b. These compounds were obtained similarly from the xanthenediones 1a,b.
3
2

3
,3,6,6,9,10-Hexamethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridinium Perchlorate (6c). A mixture
of compound 5b (3.77 g, 10 mmol) and 2-propanol (20 ml), containing methylamine (1.55 g, 50 mmol), was
boiled with a reflux condenser for 7 h. It was then cooled, and 70% perchloric acid (2 ml) was carefully added.
After 4 h absolute ether (100 ml) was added to the solution, and the precipitate was filtered off, washed with
ether, and dried. The product was recrystallized from isopropyl alcohol.
Salt 6a. This salt was obtained similarly from the perchlorate 5a. If the methylamine is replaced by an
equivalent amount of aniline the salt 6b is formed.
9
-(4-Methoxyphenyl)-3,3,6,6,10-pentamethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridinium
Perchlorate (6d). A mixture of acridinedione 7d (4.01 g, 10 mmol), acetic anhydride (15 ml), and perchloric
acid (calculated on 100% HClO ) (10 mmol) was boiled with a reflux condenser for 6 h. It was then cooled, and
4
absolute ether (100 ml) was added. The oily precipitate was separated, isopropyl alcohol (10 ml) was added, and
the mixture was heated to boiling and cooled. The product was recrystallized from isopropyl alcohol.
Perchlorates 6a-c. These compounds were obtained similarly from the xanthenediones 7a-c.
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3