Synthesis of 9-R1-10-R-1,8-dioxo-decahydroacridines and dioximes based on them

Article abstract of DOI:10.1023/A:1013845426393

3,3,6,6-Tetramethyl-9-R¹-10-R-1,8- dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridines were synthesized through the intermediate α-R-methylenebisenamino ketones by the condensation of 5,5-dimethyl-3-N-R-aminocyclohex-2-enones with aliphatic, aromatic, and furan aldehydes (2-propanol, phosphorus pentoxide). It was found that the degree of substitution of the heterocycle in decahydroacridinediones has an effect on the direction of their transformations during oximation.

Full text of DOI:10.1023/A:1013845426393

Chemistry of Heterocyclic Compounds, Vol. 37, No. 10, 2001
SYNTHESIS OF 9-R1-10-R-1,8-DIOXO-
DECAHYDROACRIDINES AND
DIOXIMES BASED ON THEM
Yu. M. Shchekotikhin, Yu. A. Getmanenko, T. G. Nikolaeva, and A. P. Kriven'ko
3,3,6,6-Tetramethyl-9-R1-10-R-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridines were synthesized
through the intermediate α-R-methylenebisenamino ketones by the condensation of 5,5-dimethyl-3-N-R-
aminocyclohex-2-enones with aliphatic, aromatic, and furan aldehydes (2-propanol, phosphorus
pentoxide). It was found that the degree of substitution of the heterocycle in decahydroacridinediones
has an effect on the direction of their transformations during oximation.
Keywords: 3-aminocyclohex-2-enone, 1,8-dioxodecahydroacridine dioxime, 1,8-dioxooctahydro-
acridinium chloride dioxime, methylenebis-3-aminocyclohex-2-enone, condensation, oximation.
The condensation of 5,5-dimethyl-3-methylamino-2-cyclohex-1-one (1a) with various aldehydes in a
20% solution of phosphorus pentoxide in isopropyl alcohol is a preparative method for the synthesis of 9-R1-10-
methyl-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridines [1]. In the present work we give new data on the
analogous reaction of the cyclic enaminoketones 1b-d, containing primary and secondary N-phenyl- and
N-benzylamino groups, with formaldehyde, aromatic aldehydes (benzaldehyde, 4-methoxybenzaldehyde,
4-hydroxy-3-methoxybenzaldehyde), and 5-nitrofurfural and also of the enamino ketone 1a with acetaldehyde. It
was established that in all cases, irrespective of the structure of the reagents, the reaction products are the
substituted 9-R1-10-R-1,8-dioxodecahydroacridines 2a-l. The yields of compounds 2 are 79-97% with the
aliphatic and aromatic aldehydes and 61-69% with 5-nitrofurfural. The new 1,8-dioxodecahydroacridines
2c,d,g-l and the previously known compounds 2a,b,e,f were obtained with yields 1.5-3 times higher than
presented in [2-5].
R1
O
O
O
R1CHO
+
Me
Me
Me
Me
Me
Me
P2O5 in i-PrOH
NHR
N
1a–d
R
2a–l
1a R = Me, b R = H, c R = Ph, d R = PhCH2; 2a-d R = H, a R1 = H, b R1 = Ph,
c R1 = 4-HO-3-MeO-C6H3, d R1 = 5-NO2-2-Fur; e R = R1 =Me; f–h R = Ph, f R1 = H,
g R1 = 4-MeOC6H4, h R1 = 5-NO2-2-Fur; i-l R = PhCH2, i R1 = H, j R1 = Ph;
k R1 = 4-MeOC6H4, l R1 = 5-NO2-2-Fur
__________________________________________________________________________________________
Saratov State University, Saratov, Russia; e-mail: sorokin@sccnit.saratov.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 10, pp. 1344-1349, October, 2001. Original article submitted
September 23, 1999. Revision submitted January 27, 2000.
1228
0009-3122/01/3710-1228$25.00©2001 Plenum Publishing Corporation

The intermediates of the reaction are α-R-methylenebisenamino ketones
3. Thus, the bisenamino ketones
3a,b were isolated with yields of 68-71% in the reaction of the enamino ketones 1a,d with formaldehyde in
isopropyl alcohol. When subsequently heated in a 20% solution of phosphorus pentoxide in isopropyl alcohol the
products underwent cyclization with the formation of the decahydroacridinediones 2i,m with yields of 91-95%.
O
O
O
O
–RNH2
Me
Me
Me
Me
Me
1a–d
CH O
Me
Me
+
2
P2O5 in i-PrOH
i-PrOH Me
NH HN
N
R
R
R
3a,b
2i,m
2i, 3a R = PhCH2, 2m, 3b R = Me
The functional derivatives of the 1,8-dioxodecahydroacridines have hardly been described at all in the
literature. The only example is the paper [3], in which it was pointed out that the formation of the dioximes of
9,10-unsubstituted and 9-aryl-substituted 1,8-dioxodecahydroacridines is accompanied by oxidation of the
1,4-dihydropyridine fragment. Dry pyridine was used as solvent. We studied the special features of the
oximation of the 10- and 9,10-substituted decahydroacridinediones 2e-g,m,n on heating in isopropyl alcohol. It
was found that under these conditions the dioximes are formed with oxidation or with retention of the
1,4-dihydropyridine ring, depending on the number of substituents at positions 9 and 10 of the substrate.
A special feature of the oximation of the 10-substituted decahydroacridinediones 2f,m, as also of the
analogs unsubstituted at the nitrogen atom [3], is aromatization of the 1,4-dihydropyridine ring, leading to the
dioximes of 10-R-1,8-dioxo-sym-octahydroacridinium chlorides 4a,b (yields 80-82%). In the case of
decahydroacridinedione 2a unsubstituted at positions 9, 10 for comparison it was shown that its dioxime is
formed with an identical result both in dry pyridine [3] and in isopropyl alcohol solution (yield 76%). The
reaction of 9-R1-10-R-1,8-dioxodecahydroacridines 2e,g,n with hydroxylamine hydrochloride takes place with
retention of the heterocycle; the presence of the 9,10 substituents probably increases its resistance to oxidation.
Dioximes 6a-c are formed with yields of 79-88%. During their preparation it is advisable to add sodium
NOH
NOH
2f,m
Me
Me
+
N
R
Me
Me
_
Cl
4a,b
R1
O
O
NOH
NOH
.
NH2OH HCl
2a
Me
Me
Me
Me
Me
Me
Me
Me
i-PrOH
N
N
R
5
2a,e–g,m,n
R1
NOH
NOH
2e,g,n
Me
Me
AcONa
Me
Me
N
R
6a–c
2n R = Me, R1 = 4-MeOC6H4; 4a R = Ph, b R = Me;
6a R1 = 4-MeOC6H4, R = Ph; b R = R1 = Me; c R = Me, R1= 4-MeOC6H4
1229

acetate to the reaction mixture in order to combine with the released hydrogen chloride, and this reduces the
reaction time by half. The structure of the decahydroacridinediones 2a-m, bisenaminoketones 3a,b, and
1
dioximes 4a,b, 6a-c was confirmed by the IR and H NMR spectra, and in the case of compounds 2a,b,e,f,i,m,
3b, 5 it was also confirmed by comparison of their melting points with published data.
The IR spectra of compounds 2a-m are characterized by the presence of two strong absorption bands in
the regions of 1590-1615 and 1640-1660 cm-1, corresponding to the stretching vibrations of the C=C–C=O
system of bonds. In the spectra of 9-(5-nitro-2-furyl)decahydroacridinediones 2d,h,l the stretching vibrations of
the nitro group are at 1500 and 1358 cm-1, while those of the furan ring are at 3100-3116 cm-1. The spectra of
the dioximes 4-6 contain a broad strong absorption band in the region of 3200-3400 cm-1, which confirms the
presence of the associated hydroxyl group. The stretching vibrations of the C=C–C=N fragment appear in the
spectra of the dioximes 6a-c in the form of two bands at 1560-1580 and 1600-1610 cm-1.
1
The H NMR spectra of the 1,8-dioxodecahydroacridines 2a-l and the dioximes 4a,b and 6a-c
correspond to their structures (Table 1).
1
TABLE 1. The H NMR Spectra of 9-R1-10-R-Decahydroacridine-1,8-
diones 2a-l and Dioximes 4a,b, 6a-c
Chemical shifts, δ, ppm, SSCC (J), Hz
Com-
2,2-H2,
4,4-H2,
pound
9,9-H2 / 9-H C(CH3)2, s
Other signals
6
7,7-H2, s 5,5-H2, 4H, s
1
2
3
4
5
2.30 (4H)
2.35 (4H)
2.19
2.19
3.21 (2H, s)
5.07 (1H, s)
1.06 (12H) 9.12 (1H, s, NH)
2a
2b
0.97 (6H),
8.17 (1H, br. s, NH);
1.08 (6H)
7.20-7.30 (5H, m, HPh)
2.45 (4H)
2.20
4.66 (1H, s)
1.00 (6H),
1.10 (6H)
9.47 (1H, br. s, OH);
8.18 (1H, s, NH);
2c
6.69-6.98 (3H, m, HAr);
3.88 (3H, s, OMe)
2.37 (4H)
2.20
2.23
5.34 (1H, s)
0.98 (6H),
1.06 (6H)
8.28 (1H, br. s, NH);
2d
2e
7.21 (1H, d, J = 4.0, HHet);
6.50 (1H, d, J = 4.0, HHet
)
2.35 (2H),
2.45 (2H)
2.21 (4H)
2.45 (4H)
4.05 (1H, m) 1.06 (6H),
1.10 (6H)
3.25 (2H, s)
5.22 (1H, s)
3.21 (3H, s, NMe);
0.84 (3H, d, J = 6.5; 9-Me)
1.92
2.16
0.97 (12H) 7.20-7.43 (5H, m, HPh)
2f
2g
0.99 (6H),
7.29-7.54 (5H, m, HPh);
7.23 (2H, d, J = 8.4, 3',5'-HAr);
6.76 (2H, d, J = 8.4, 2',6'-HAr);
3.74 (3H, s, OMe)
1.09 (6H)
2.22 (4H)
2.30 (4H)
2.05
5.52 (1H, s)
0.83 (6H),
0.97 (6H)
7.51-7.59 (5H, m, HPh);
2h
7.21 (1H, d, J = 3.7, HHet);
6.55 (1H, d, J = 3.7, HHet
)
2.17
2.20
3.45 (2H, s)
5.34 (1H, s)
1.00 (6H),
1.05 (6H)
7.23-7.29 (5H, m, HPh);
2i
2j
4.65 (2H, s, NCH2)
2.36 (2H),
2.43 (2H)
2.35 (2H),
2.42 (2H)
0.89 (6H),
7.11-7.41 (10H, m, HPh);
4.90 (2H, s, NCH2)
0.99 (6H)
2.18
5.26 (1H, s)
0.88 (6H),
0.98 (6H)
7.31 (2H, d, J = 8.8, 3',5'-HAr);
7.15-7.23 (5H, m, HPh);
6.71 (2H, d, J = 8.8, 2',6'-HAr);
4.89 (2H, s, NCH2);
2k
3.72 (3H, s, OMe)
2.42 (4H)
2.36 (4H)
2.23
2.24
5.54 (1H, s)
3.29 (2H, s)
0.87 (6H),
1.02 (6H)
7.30-7.41 (5H, m, HPh);
7.25 (2H, d, J = 3.6, HHet);
6.60 (2H, d, J = 3.6, HHet);
4.95 (2H, s, NCH2)
2l
1.06 (12H) 3.21 (3H, s, NMe)
2m
1230

TABLE 1 (continued)
1
2
3
4
5
6
2.90 (4H)
2.76
9.56 (1H, s)
1.12 (12H) 7.90 (3H, m, HPh);
7.37 (2H, m, HPh)
4a
3.00 (4H)
2.78 (4H)
2.82
2.28
9.54 (1H, s)
5.34 (1H, s)
1.26 (12H) 3.96 (3H, s, NMe)
4b
6a
1.05 (6H),
7.72 (5H, m, HPh);
1.16 (6H)
7.38 (2H, d, J = 8.4, 3',5'-HAr);
7.10 (2H, d, J = 8.4, 2',6'-HAr);
4.02 (3H, s, OMe)
2.76 (4H)
2.77 (4H)
2.40
2.48
5.23 (1H, s)
1.22 (12H) 7.29 (2H, d, J = 8.2, 3',5'-HAr);
7.02 (2H, d, J = 8.2, 2',6'-HAr);
3.97 (3H, s, OMe);
6b
6c
3.61 (3H, s, NMe)
4.11 (1H, m) 1.22 (12H) 3.59 (3H, s, NMe);
1.12 (3H, d, J = 6.2, 9-Me)
The most characteristic for these compounds are the signals of the protons at the C(9) atom. In the
spectra of the decahydroacridinediones 2a,f,i,m they are in the region of 3.21-3.29, while for compounds
2b-e,g,h,j-l and the dioximes 6a-c they are at 4.05-5.54 ppm. For the dioximes of 1,8-dioxooctahydroacridinium
chlorides 4a,b there is a downfield shift of the signal for the proton at the C(9) atom (9.54-9.56 ppm).
Our results [1] make it possible to propose a preparative method for the synthesis of 9-R1-10-R-1,8-
dioxodecahydroacridines and to investigate the special characteristics of their chemical behavior during oximation.
TABLE 2. The Characteristics of the Synthesized Compounds
Found, %
——————
Com-
Empirical
Calculated, %
mp, ºС
Yield, %
pound formula
С
H
N
C24H29NO4
72.91
72.73
7.34
7.59
3.54
3.47
226-228
245-247
225-226
239-241
184-185
178-179
243-245
130-132
>350
84
69
79
61
85
81
67
68
80
82
82
79
88
2с
C21H24N2O5
C30H33NO3
C27H28N2O5
C30H33NO2
C31H35NO3
C28H30N2O5
C31H38N2O2
C23H28ClN3O2
C18H26ClN3O2
C30H35N3O3
C19H29N3O2
C25H33N3O3
65.57
6.28
7.25
2d
2g
2h
2j
65.63
6.25
7.29
79.31
79.12
7.40
7.25
3.29
3.08
70.75
6.18
6.34
70.43
6.09
6.09
82.29
82.00
7.79
7.52
3.65
3.19
78.95
7.61
3.39
2k
2l
79.28
7.51
2.98
71.05
70.89
6.21
6.33
6.07
5.91
79.57
8.38
6.07
3a
4а*
4b*
6a
6b
6c
79.75
8.09
5.96
67.14
66.75
6.62
6.77
10.70
10.16
61.71
7.56
12.07
>350
61.45
7.40
11.95
74.59
74.23
7.46
7.22
9.02
8.66
274-276
264-265
256-257
69.07
8.58
12.34
68.88
8.76
12.69
71.38
70.92
7.93
7.80
10.07
9.93
_______
* For compound 4a, Cl found, %: 9.00; Cl calculated, %: 8.59.
For compound 4b, Cl found, %: 10.18; Cl calculated, %: 10.10.
1231

EXPERIMENTAL
The IR spectra were recorded on a Specord M-80 instrument for suspensions in Vaseline oil or
hexachlorobutadiene. The 1H NMR spectra were obtained on a Varian FT-80A spectrometer in
deuterochloroform (compounds 2a-m) and deuterotrifluoroacetic acid (compounds 4a,b, 6a-c) 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.
Enamino ketones 1a-d were synthesized by the method described in [7], and compound 2n by the
method in [1].
3,3,6,6-Tetramethyl-9-(5-nitro-2-furyl)-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-dione (2d).
Enamino ketone 1b (2.78 g, 0.02 mol) was added to a solution of phosphorus pentoxide (8 g) in isopropyl
alcohol (40 ml). The mixture was heated until a transparent solution had formed, and 5-nitrofurfural (1.41 g,
0.01 mol) was added. The reaction mass was boiled with a reflux condenser for 10-12 h and was then poured
into 300 ml of cold water. After 12 h the precipitated compound 2d was filtered off, washed with water, and
recrystallized from ethanol.
Decahydroacridinediones 2a-c,f-j were obtained similarly. The characteristics and yields of the
compounds 2b,d,g,h,j-l obtained for the first time are presented in Table 2.
The yields, melting points, and published characteristics for the previously described compounds
2a,b,e,f,i are as follows: 2a yield 79%, mp 301-303°C (52%, 303-306°C [2]); 2b yield 89%, mp 290-291°C
(74%, 290-292°C [3]); 2e yield 76%, mp 215-217°C (38%, 215-217°C [4]); 2f yield 86%, mp 289-291°C (43%,
289-291°C [5]); 2i yield 93%, mp 169-171°C (93%, 168-170°C [1]).
Methylenebis-2,2'-(5,5-dimethyl-3-methylaminocyclohex-2-enone) (3a). A mixture of the enamino
ketone 1d (4.58 g, 0.02 mol), paraform (0.3 g, 0.01 mol), and isopropyl alcohol (40 ml) was boiled under a
reflux for 2 h and was then poured into cold water (200 ml). The precipitate was filtered off and recrystallized
1
from isopropyl alcohol, and 3.20 g (68%) of compound 3a was obtained; mp 130-132°C (ethanol). H NMR
), δ, ppm,
spectrum (CDCl3
J (Hz): 9.36 (2H, br. s, NH); 7.24 (10H, m, HPh); 4.48 (4H, d, J = 6.4, N–CH2);
3.44 (2H, s, CH2); 2.20 (4H, s, 2CH2); 2.14 (4H, s, 2CH2); 0.92 (12H, s, 4CMe2).
Similarly, from the enamino ketone 1a compound 3b was obtained. Yield 71%; mp 222-223°C.
Published data: mp 223-224°C [6]. H NMR spectrum (CDCl3
1
), δ, ppm.
J (Hz): 9.21 (2H, bs, NH); 3.25 (2H, s,
CH2); 2.91 (6H, d, J = 5.1, 2NMe); 2.25 (4H, s, 2CH2); 2.18 (4H, s, 2CH2); 1.03 (12H, s, 4CMe2).
3,3,6,6-Tetramethyl-10-benzyl-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-dione (2i). A sample of
compound 3a (2.35 g, 0.005 mol) was added to a solution of phosphorus pentoxide (4 g) in isopropyl alcohol
(20 ml). The mixture was boiled with a reflux condenser for 2 h and was then poured into water (200 ml). The
precipitate was filtered off and recrystallized from isopropyl alcohol. We obtained 1.51 g (91%) of compound
2i; mp 169-171°C. Published data: mp 168-170°C [1].
Compound 2m was obtained similarly from the bisenamino ketone 3b. Yield 95%; mp 247-249°C.
Published data: 247-249°C [6].
Dioxime of 3,3,6,6-Tetramethyl-10-phenyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridinium Chloride
(4a). A mixture of the decahydroacridinedione 2f (3.49 g, 0.01 mol), hydroxylamine hydrochloride (4.17 g,
0.06 mol), and isopropyl alcohol (50 ml) was boiled with a reflux condenser for 4 h. The precipitated compound
4a was filtered off, washed with water, and recrystallized from ethanol.
Dioxime 4b was obtained similarly from the decahydroacridinedione 2m.
p
Dioxime of 3,3,6,6-Tetramethyl-9-( -methoxyphenyl)-10-phenyl-1,2,3,4,5,6,7,8,9,10-decahydro-
acridine-1,8-dione (6a). A mixture of compound 2g (4.55 g, 0.01 mol), hydroxylamine hydrochloride (2.78 g,
0.04 mol), sodium acetate (3.28 g, 0.04 mol), and isopropyl alcohol (50 ml) was boiled with a reflux condenser
for 4-5 h. It was then cooled and poured into 300 ml of cold water. The precipitated compound 6a was filtered
off, washed with water, and recrystallized from ethanol.
1232

Dioximes 6b,c, 5 were obtained similarly from the decahydroacridinediones 2a,e,n.
The characteristics and yields of the dioximes 4a,b and 6a-c are given in Table 2. The known dioxime 5
was obtained with a yield of 76%. Its melting point (280°C) agreed with published data [3].
REFERENCES
1.
T. G. Nikolaeva, Yu. M. Shchekotikhin, A. S. Ponomarev, and A. P. Kriven'ko, Khim. Geterotsikl.
Soedin., 475 (2000).
2.
3.
4.
5.
6.
7.
A. A. Bakibaev and V. D. Filimonov, Zh. Org. Khim., 27, 854 (1991).
G. Ya. Vanag and E. I. Stankevich, Zh. Obshch. Khim., 30, 3287 (1960).
E. I. Stankevich, E. E. Grinshtein, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., 228 (1975).
A. A. Bakibaev and V. D. Filimonov, Zh. Org. Khim., 27, 223 (1991).
J. V. Greenhill, J. Chem. Soc. Chem. Commun., C, 2699 (1971).
O. Ya. Neiland, Izv. Akad. Nauk. Latv. SSR. Ser. Khim., 557 (1964).
1233