Synthesis and rotamerism of 9,10-diarylsubstituted 1,2,3,4,5,6,7,8,9,10- decahydroacridine-1,8-diones

Article abstract of DOI:10.1023/B:COHC.0000033541.49115.a0

Condensation of aromatic aldehydes with 5,5-dimethylcylohexane-1,3-dione and primary arylamines gave 9,10-diaryl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8,9, 10-decahydroacridine-1,8-diones. Several stereochemical features of the synthesized compounds are discu

Full text of DOI:10.1023/B:COHC.0000033541.49115.a0

Chemistry of Heterocyclic Compounds, Vol. 40, No. 4, 2004
SYNTHESIS AND ROTAMERISM OF
9,10-DIARYL-SUBSTITUTED
1,2,3,4,5,6,7,8,9,10-DECAHYDRO-
ACRIDINE-1,8-DIONES
V. A. Chebanov1, V. E. Saraev1, K. M. Kobzar'1, S. M. Desenko1, V. D. Orlov2, and E. A. Gura1
Condensation of aromatic aldehydes with 5,5-dimethylcylohexane-1,3-dione and primary arylamines
gave 9,10-diaryl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-diones. Several
stereochemical features of the synthesized compounds are discussed. Dynamic NMR was used to
determine the inversion barriers for the rotamers formed.
Keywords: diaryl-substituted decahydroacridinediones, heterocyclization, rotamerism.
9,10- Disubstituted decahydroacridine-1,8-diones are generally prepared through a Hanztsch synthesis
with a wide variety of reaction conditions [1-5]. The synthesis of the target products consists of two stages: the
reaction of cyclic ketones with aldehydes and the separation of the Michael adducts followed by their
heterocyclization using primary amines. Moreover, the Michael adducts are quite readily cyclized to
octahydroxanthones and the second stage of the reaction is almost always accompanied by the formation of quite
large amounts of oxygen containing heterocycles.
One of the problems in this work was the development of a single stage method for obtaining the target
9,10-disubstituted decahydroacridine-1,8-diones. Based on general and systematized data [1-8] and certain
experimental data we propose
a single stage method for the synthesis of diaryl substituted
decahydroacridinediones which is more convenient to carry out and gives a higher yield of the final products
than does the two stage.
The procedure consists of the reaction of 5,5-dimethylcyclohexane-1,3-dione (1, dimedone) with the
aldehydes 2a-i and the primary amines 3a-i. The selection of reaction conditions (in particular the solvent and
the catalyst) appears to the most critical. The reactions in alcohols and slow boiling solvents is independent of
the type of catalyst and gives difficult to separate mixtures of the reaction products and the starting materials.
The use of the high boiling, polar DMF as solvent appears optimal. It was found that the basic catalysts given in
the literature (triethylamine, N-methylmorpholine, piperidine) have little effect and the reaction products are
mainly the Michael adducts 4. At the same time, a large amount of acid catalyst (acetic, trifluroacetic,
hydrochloric acid) leads to a heavy contamination of the target compounds 5a-o by the xanthones 6. In the
method proposed by us a small amount of concentrated hydrochloric acid is used.
__________________________________________________________________________________________
1
NTK Institute for Single Crystals, Kharkov 61001, Ukraine e-mail: chebanov@isc.kharkov.com.
2 Kharkov National University, Kharkov 61077, Ukraine e-mail: orlov@univer.kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 571-576, April, 2004. Original article submitted October
23, 2002; revision submitted October 29, 2003.
0009-3122/04/4004-0475©2004 Plenum Publishing Corporation
475

O
NH2
O
H
DMF, AcOH, ∆
R1
R2
+
+
Ar
Me
O
Me
2a–i
1
3a–i
Ar
OH
OH
Me
Me
Me
O O
Me
4a–i
O
O
Ar
O
Ar
O
Me
Me
Me
+
Me
Me
Me
O
N
Me
Me
R2
6a–i
R1
5a–o
2, 4, 6 a Ar = Ph; b Ar = 3-FC6H4; c Ar = 4-MeC6H4; d Ar = 4-BrC6H4; e Ar = 4-ClC6H4;
f Ar = 4-O2NC6H4; g Ar = 2-MeO-5-BrC6H3; h Ar = 4-FC6H4; i Ar = 4-MeOOCC6H4;
3 a–c,h,i R1 = H, a R2 = H, b R2 = 4-OEt, c R2 = 2-F, h R2 = 3-CO2H, i R2 = 3-F; d R1 = 6-F, R2 = 2-F; e R1 = 3-Cl, R2 = 2-Cl;
f R1 = 4-Cl, R2 = 2-Cl; g R1 = 4-OMe, R2 = 2-OMe; 5 a-g,n,o R1 = H; a Ar = Ph, R2 = H, b Ar = 3-FC6H4, R2 = 4-OEt,
c–g R2 = 2-F, c Ar = Ph, d,l Ar = 4-MeC6H4, e Ar = 4-BrC6H4, f,i,k,m Ar = 4-ClC6H4, g Ar = 4-O2NC6H4,
n Ar = 4-FC6H4, R2 = 3-CO2H, o Ar = 4-MeOOCC6H4, R2 = 3-F; h Ar = 2-MeO-5-BrC6H3,
R1 = 6-F, R2 = 2-F; i–l R2 = 2-Cl, i, j R1 = 3-Cl, j Ar = 2-MeO-5-BrC6H3, k,l R1 = 4-Cl,
m R1 = 4-OMe, R2 = 2-OMe
The composition and structure of the synthesized 9,10-diaryl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8,9,10-
1
decahydroacridine-1,8-diones 5a-o were confirmed by elemental analytical data (Table 1) and by H NMR
spectroscopy (Table 2). The reaction products 4a-i and 6a-i were not specifically separated from the reaction
1
mixture but their presence was revealed using TLC and H NMR. Samples of compounds 4a-i and 6a-i were
prepared for comparison by known methods [2-5].
1
The H NMR spectra of compounds 5a-o show singlets at 0.68 and 0.90 ppm which are assigned to the
protons of the four methyl groups in positions 3 and 6, multiplets for the CH2 group protons of the cyclohexane
rings in the range 1.42-2.40 ppm, a singlet for the methine proton at 4.93-5.28 ppm, and signals for the aromatic
protons in the range 6.60-8.10 ppm, and also for the substitutent in Ar and R1, R2.
At room temperature the spectra of the compounds 5c-g, i-m with one ortho substituent in N–Ar
(R1 = H, 2-R2 ≠ H) show a doubling of virtually all of the signals, in particular the methine proton and the methyl
group protons. This led us to infer the presence of two diastereomers differing in the relative orientation of the
substituents Ar and R2 relative to the plane of the acridine framework, hence showing that the rotamers A and B
have quite a high inversion barrier:
476

O
Ar
O
O
Ar
N
O
9
10
N
R2
R2
F
B
1
In order to verify this proposal we have studied the dependence of the H NMR spectra for the
synthesized compounds on temperature. With a temperature increase we have found that the plotted doubling of
the signals in the spectra of the acridinediones 5c-g, i-m is gradually lost until they coalesce completely.
Measurement of the spectra at -60°C for the acridinediones 5n,o (R1 = H and 3-R2 ≠ H) gives a doubling of the
signals which is not seen at room temperature. In the case of compounds 5a,b an increase (from -60 to 160°C)
and lowering of the temperature does not affect the appearance of the spectrum. For compound 5h
(2-R1 = 6-R2 ≠ H) the existence of rotamers is not possible and a doubling of signals is not observed in the
temperature range indicated above.
1
The dependence of the H NMR spectra of compounds 5c-g on temperature allowed an experimental
determination of their energetic inversion barriers ∆G1 in kJ/mol as 82±5 (5c,d), 82±6 (5e), 81±6 (5f), and 84±5
(5g). This high barrier is not typical of biphenyls and its hetero analogs [9]. In particular, they allow observation
of doubled signals even for compounds 5n,o which contain the R2 substituent in a meta position.
TABLE 1. Parameters for Compounds 5a-o
Com-
pound
Empirical
formula
Found N, %
Calculated N, %
——————
mp, °С
Yield, %
5a
5b
5c
5d
5e
5f
C29H31NO2
3.21
3.29
2.82
2.87
3.15
3.16
3.10
3.06
2.62
2.68
3.01
2.93
5.72
5.70
2.50
2.46
2.61
2.65
2.40
2.32
2.71
2.65
2.81
2.75
2.73
2.69
2.91
2.87
2.83
2.79
209-210
219-221
192-194
178-179
212-214
275-276
273-274
262-264
274-275
260-262
280-281
248-250
229-230
305-308
268-270
67
92
78
58
62
69
89
75
70
76
62
80
68
55
81
C31H34FNO3
C29H30FNO2
C30H32FNO2
C29H29BrFNO2
C29H29ClFNO2
C29H29FN2O4
C30H30 BrF2NO3
C29H28Cl3NO2
C30H30BrCl2NO3
C29H28Cl3NO2
C30H31Cl2NO2
C31H34ClNO4
C30H30FNO4
5g
5h
5i
5j
5k
5l
5m
5n
5o
C31H32FNO4
477

TABLE 2. 1H NMR Spectra of Compounds 5a-o
Chemical shift, δ, ppm (spin-spin coupling, J, Hz)
Com-
4CH2
(8Н, m)
CH
(CH3)2C*2
pound*
Harom, m
R1, R2
—
(s / two s)
5a
5b
0.70; 0.87
0.72; 0.87
1.62-2.36
1.8-2.32
5.06
5.05
6.97-7.72 (10Н)
6.75-7.45 (8Н)
1.37 (3Н, t, J = 7.3, СH3)
4.01 (2Н, q, J = 7.3, CH2)
5c
5d
5e
5f
0.73; 0.88; 0.89;
0.72; 0.75; 0.89
0.72; 0.75; 0.89
0.71; 0.74; 0.88
0.72; 0.74; 0.90
0.76; 0.88
1.56-2.35
1.57-2.37
1.59-2.36
1.57-2.35
1.61-2.40
1.69-2.29
1.46-2.30
1.42-2.26
1.42-2.33
1.45-2.28
1.53-2.29
1.45-2.35
1.63-2.35
5.01; 5.04
4.97; 5.00
4.97; 5.00
5.01; 5.02
5.14
6.95-7.74 (9Н)
6.92-7.75 (8Н)
7.16-7.76 (8Н)
7.13-7.76 (8Н)
7.36-8.22 (8Н)
6.76-7.86 (6Н)
7.14-7.98 (7Н)
6.76-7.97 (6Н)
7.10-8.10 (7Н)
6.83-8.00 (7Н)
6.60-7.50 (7Н)
6.88-7.78 (Н)
7.25-8.04 (8Н)
—
2.21 (3Н, s, СH3)
—
—
—
5g
5h
5i
5.10
3.77 (3Н, s, ОСH3)
2.15 (3Н, s, СH3)
3.80 and 3.84 (3Н, two s, OСH3)
—
2.75 and 2.78 (3Н, two s, СH3)
3.85 and 3.90 (3Н, two s, ОСH3)
—
0.75; 0.88; 0.90
0.73; 0.86
5.00; 5.02
4.97; 5.28
4.98
5j
5k
5l
0.73; 0.87; 0.89
0.71; 0.73; 0.86; 0.88
0.68; 0.73; 0.86
0.75; 0.89
5.02
5m
5n
5o
4.93; 4.99
5.02
0.68; 0.87
5.06
3.79 (3Н, s, OСH3)
_______
* Compounds 5c-g, i-m are a mixture of rotamers.
*2 Singlet signals observed with an overall intensity corresponding to 12 protons.

To explain the results obtained we have carried out a quantum-chemical analysis of the process of the
conformational transformation of the rotamers. Calculation of equilibrium geometries and the geometry of the
transition state using the AM1 method showed that the cyclohexanone ring sterically hinders the rotation of the
aryl substituent around the C–N bond. The high steric loading for compounds 5c-g, i-m infers that, in the
process of the conformational transition, simultaneously with rotation of the 10-Ar substituent the
dihydropyridine ring has to undergo a complete inversion. The initially planar disposition of bonds around the
nitrogen atoms becomes pyramidal and the cyclohexanone rings are strongly distorted. A direct result of the
occurrence of this combination of energetically unfavored processes is the high (~82 kJ/mol) barrier to
inversion.
EXPERIMENTAL
1H NMR spectra were measured on a Varian Mercury VX-200 spectrometer (200 MHz) using DMSO-d6
solvent and TMS internal standard. The purity of the compounds prepared was monitored using TLC on Silufol
UV-254 plates with chloroform, ethyl acetate or their mixture as solvent. Melting points were measured on a
Koffler stage. The nitrogen content in the prepared compounds corresponded with that calculated (Table 1).
Determination of the rotational barriers was carried out using an overall line shape method and its
comparison with the practical, least squares numerical value as in the method [10]. To determine the effective
time T2 in solution an equimolar amount of the corresponding 9-aryl-3,3,6,6-tetramethyl-2,3,4,5,6,7,8,9-
octahydro-1H-1,8-xanthenedione was added (for which T2 had been measured). Calculations were carried out on
the methyl group signals. The obtained values for the rate of rotation constant were used for calculation of ∆H≠
and ∆S≠ as line shape coefficients in the Eyring equation.
Quantum-chemical calculations were performed using the GAMESS program package [11]. The
parameters for the different atoms used in the AM1 calculation method were taken from [12, 13].
3,3,6,6-Tetramethyl-9,10-diphenyl-1,2,3,4,5,6,7,8,9,10-decahydroacridine-1,8-dione (5a). Two drops
of concentrated hydrochloric acid were added to a solution of dimedone 1 (0.42 g, 3 mmol), benzaldehyde 2a
(0.16 g, 1.5 mmol), and aniline (0.14 g, 3 mmol) in dry DMF (1 ml) and the mixture was refluxed for 3 h. The
precipitate formed on cooling was filtered off and crystallized from aqueous ethanol (80%) to give compound 5a
(0.43 g).
Compounds 5b-o were prepared similarly from dimedone 1, the aldehydes 2b-i, and the amines 3b-i.
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