Tris(pentafluorophenyl)borane-catalyzed three-component reaction for the synthesis of 1,8-dioxodecahydroacridines under solvent-free conditions

Article abstract of DOI:10.1055/s-2008-1067039

A mild and efficient method for the synthesis of 1,8- dioxodecahydroacridines has been developed. The synthesis proceeds via a three-component reaction of a 1,3-dione, an aldehyde and an amine, under solvent-free conditions, catalyzed by tris(pentafluorophenyl)borane [B(C ₆F₅)₃]. The mildness of the catalyst was demonstrated by studying the reaction of 1,3-cyclohexanedione with various aldehydes and amines which gave the 1,8-dioxo-decahydroacridines in high yields.

Full text of DOI:10.1055/s-2008-1067039

PAPER
1737
Tris(pentafluorophenyl)borane-Catalyzed Three-Component Reaction for the
Synthesis of 1,8-Dioxodecahydroacridines under Solvent-Free Conditions
Solvent-Free
S
r
ynthesis
i
of 1,8-
v
Dioxodecah
a
ydroacridin
r
es i Chandrasekhar,* Yaragorla Srinivasa Rao, Lella Sreelakshmi, Bodugam Mahipal, Chada Raji Reddy
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: srivaric@iict.res.in
Received 8 January 2008; revised 22 February 2008
R1CHO
O
O
R1
O
Abstract: A mild and efficient method for the synthesis of 1,8-di-
oxodecahydroacridines has been developed. The synthesis proceeds
via a three-component reaction of a 1,3-dione, an aldehyde and an
amine, under solvent-free conditions, catalyzed by tris(pentafluo-
rophenyl)borane [B(C6F5)3]. The mildness of the catalyst was
demonstrated by studying the reaction of 1,3-cyclohexanedione
with various aldehydes and amines which gave the 1,8-dioxo-
decahydroacridines in high yields.
2a–i
B(C6F5)3 (3 mol%)
neat, r.t., 1.5–3 h
R2NH2
O
N
3a,b
R2
1
R
1 = aryl or alkyl
R2 = aryl
4a–j
Scheme 1
Key words: Hantzsch reaction, acridinediones, tris(pentafluo-
rophenyl)borane, three-component reaction, Lewis acid
cance, the synthesis of this class of compounds under mild
conditions is of importance. Herein, we report the facile
synthesis of 1,8-dioxodecahydroacridines using tris(pen-
tafluorophenyl)borane [B(C6F5)3] (Scheme 1), which is
being pursued as a nonconventional and mild catalyst.
Previously, we have shown the efficiency of this catalyst
in various organic transformations, among others.12,13
The 1,4-dihydropyridine (DHP) ring system is found in a
variety of compounds including dyes,1 organic materials
and pharmaceuticals.2 Among the pharmaceuticals, 1,4-
dihydropyridine derivatives have been employed for the
treatment of platelet antiaggregatory activity,2c Alz-
heimer’s disease,2c tumors,2d cardiovascular diseases in-
cluding hypertension3 and diabetes.4 In addition, the
hydrogenation and the oxidation of these derivatives to
potentially useful pyridine compounds has also been ex-
tensively investigated.5
We first examined the reaction of 1,3-cyclohexanedione
(1) with benzaldehyde (2a) and aniline (3a). When this re-
action was performed in the presence of B(C6F5)3 (3
mol%) under solvent-free reaction conditions at room
temperature for 1.5 hours, the desired 1,8-dioxodecahy-
droacridine 4a was isolated in 90% yield (Table 1, entry
1). The application of this procedure to a variety of sub-
strates (aldehydes and amines) was investigated and the
results are summarized in Table 1. Various aldehydes,
such as aromatic, heteroaromatic and aliphatic aldehydes
(2a to 2i), could also participate in the reaction with 1,3-
cyclohexanedione (1) and aniline (3a) or 4-fluoroaniline
(3b) to give the corresponding acridinedione products 4a
to 4j in good yields (Table 1, entries 1 to 10). It is worth
noting the efficiency of B(C6F5)3 in a reaction with ammo-
nium acetate (3c); namely, treatment of 1,3-cyclohex-
anedione (1) with benzaldehyde (2a) and 3c provided the
N-unsubstituted 9-phenyl-1,8-dioxodecahydroacridine
(4k) in 80% yield, which could be further N-alkylated to
make more derivatives (Table 1, entry 11). Similarly, ali-
phatic aldehyde 2e also participated in the reaction with 1
and ammonium acetate (3c) to give 4l in 78% yield
(Table 1, entry 12).
Based on the importance, the synthesis of polyfunctional-
ized 1,4-dihydropyridine derivatives has been extensively
studied, in particular the Hantzsch reaction since its dis-
covery in 1882.6 This method involves a three-component
condensation of an aldehyde with ethyl acetoacetate and
ammonia in either acetic acid or refluxing alcohol; how-
ever, long reaction times, the use of volatile solvents and
low yields of product are drawbacks of this method. Later,
a number of modified methods using various catalysts un-
der improved conditions7 have been developed to over-
come these drawbacks for the synthesis of various 1,4-
dihydropyridines. It is still desirable to develop a catalyst
that can tolerate various substrates. This is particularly so
for the synthesis of 1,8-dioxodecahydroacridines which
have received less attention than other 1,4-dihydropyri-
dine derivatives.1a,8 These acridinediones, which have
been shown to have very high lasing efficiencies, are also
interesting in view of the electrochemical behavior8b,9 of
heterocyclic compounds and in the interaction with
DNA.10 Their analogues show potent antimalarial activi-
ty.11 Very few methods are known in the literature for the
synthesis of acridinediones. In view of the above signifi-
A comparative study was carried out using other common
Lewis acids, such as BF3·OEt2, AlCl3 and ZnCl2, as cata-
lysts and the results obtained are summarized in Table 2.
Thus, the reaction of 1,3-cyclohexanedione (1) with benz-
aldehyde (2a) and aniline (3a) in the presence of BF3·OEt2
(3 mol%) at room temperature afforded the desired prod-
uct 4a in only 58% yield after two hours, while with 3
mol% of AlCl3 the yield of the product 4a was 63%
SYNTHESIS 2008, No. 11, pp 1737–1740
x
x.
x
x
.
2
0
0
8
Advanced online publication: 29.04.2008
DOI: 10.1055/s-2008-1067039; Art ID: Z00108SS
© Georg Thieme Verlag Stuttgart · New York

1738
S. Chandrasekhar et al.
PAPER
Table 1 B(C6F5)3-Catalyzed Three-Component Reaction of 1,3-Cyclohexanedione, an Aldehyde and an Amine for the Synthesis of
1,8-Dioxodecahydroacridines under Solvent-Free Conditions
Entry
1
Aldehyde
Amine
Producta
Time (h)
1.5
Yieldb (%)
Mp (°C)
274–276
CHO
NH2
4a
90
2a
3a
3a
CHO
2
3
4b
4c
1.5
2.0
89
86
270–272
214–216
OMe
2b
CHO
3a
3a
Br
2c
CHO
N
4
5
4d
4e
3.0
2.5
78
82
218–210
176–178
2d
CH3CH2CHO
2e
3a
NH2
CH3(CH2)4CHO
2f
6
4f
2.8
80
198–200
F
3b
CH3(CH2)3CHO
2g
7
8
9
3b
3a
3b
4g
4h
4i
3.0
3.0
2.5
83
78
75
202–204
199–200
186–188
CH3(CH2)4CHO
2f
CH3CHO
2h
CHO
10
3a
4j
3.0
76
256–258
F
2i
PhCHO
2a
NH4OAc
3c
4k
(R2 = H)
11
12
2.8
3.0
80
78
279–281
262–264
CH3CH2CHO
2e
4l
3c
(R2 = H)
a All the products were characterized by 1H NMR, 13C NMR, and IR spectroscopy and mass spectrometry.
b Isolated yields.
(Table 2, entries 1 and 2). ZnCl2 (3 mol%) was also found In conclusion, the present study clearly demonstrates the
to be effective for this conversion, providing 4a in a rea- efficiency of tris(pentafluorophenyl)borane as a Lewis
sonably good yield (78%; Table 2, entry 3). Among the acid catalyst in the synthesis of substituted 1,8-dioxo-
tested catalysts, B(C6F5)3 was found to be mildest and decahydroacridines in high yields. The milder, solvent-
most effective in terms of yield (90%) and reaction profile free, room-temperature reaction conditions and shorter re-
(Table 2, entry 4).
action times are notable features of this procedure when
compared to the other methods reported in the literature.
Synthesis 2008, No. 11, 1737–1740 © Thieme Stuttgart · New York

PAPER
Solvent-Free Synthesis of 1,8-Dioxodecahydroacridines
1739
1H NMR (200 MHz, CDCl3): d = 7.60–7.34 (m, 5 H), 7.30–7.17 (m,
4 H), 5.32 (s, 1 H), 2.40–1.75 (m, 12 H).
Table 2 Reaction of 1,3-Cyclohexanedione (1) with Benzaldehyde
(2a) and Aniline (3a) in the Presence of Different Lewis Acid Cata-
lysts
13C NMR (75 MHz, CDCl3): d = 196.1, 152.0, 149.0, 139.0, 130.7,
129.9, 129.6, 129.3, 127.0, 122.5, 115.2, 36.8, 32.2, 28.4, 21.2.
Entry
Acid catalyst (3 mol%) Time (h) Yielda (%) of 4a
HRMS (ESI): m/z calcd for C25H23NO2Br (M + H)+: 448.0912;
found: 448.0904.
1
2
3
4
BF3·OEt2
AlCl3
2
58
63
78
90
3
4d
Pale-yellow solid; mp 218–210 °C.
ZnCl2
2
IR (neat): 2948, 1637, 1360, 1231, 1182 cm–1.
B(C6F5)3
1.5
1H NMR (200 MHz, CDCl3): d = 7.69–7.48 (m, 5 H), 7.46–7.19 (m,
4 H), 5.36 (s, 1 H), 2.40–1.68 (m, 12 H).
a Isolated yields, after column chromatography.
13C NMR (75 MHz, CDCl3): d = 196.1, 152.4, 145.5, 138.8, 138.5,
130.6, 129.7, 127.9, 114.5, 36.7, 31.0, 28.4, 21.2.
MS (EI): m/z = 371.2 [M + 1]+, 393.1 [M + 23]+.
Chemicals such as 1,3-cyclohexanedione, tris(pentafluorophe-
nyl)borane, aldehydes and amines were purchased from Aldrich and
were used as received. Melting points were determined with a Stuart
SMP3 apparatus. IR spectra were recorded on a Perkin–Elmer 683
4e
White solid; mp 176–178 °C.
1
spectrometer. H (200 MHz) and 13C (75 MHz) NMR spectra of
IR (neat): 2925, 2855, 1636, 1529, 1381, 1234, 1185 cm–1.
samples in CDCl3 were recorded on a Bruker Avance AV-300 spec-
trometer. Chemical shifts are reported in ppm with respect to inter-
nal TMS. Coupling constants (J) are quoted in Hz. Mass spectra
were obtained on an Agilent Technologies LC/MSD Trap SL instru-
ment.
1H NMR (200 MHz, CDCl3): d = 7.60–7.43 (m, 3 H), 7.29–7.09 (m,
2 H), 4.25 (t, J = 5.1 Hz, 1 H), 2.48–1.75 (m, 12 H), 1.08–0.76 (m,
5 H).
13C NMR (75 MHz, CDCl3): d = 196.9, 152.9, 139.4, 130.0, 129.3,
114.5, 37.1, 32.0, 29.8, 28.4, 22.8, 14.2.
1,8-Dioxodecahydroacridines 4; General Procedure
HRMS (ESI): m/z calcd for C21H23NO2Na: 344.1626; found:
344.1630.
A mixture of an aldehyde (1.0 mmol), 1,3-cyclohexanedione (2.0
mmol), an amine (1.0 mmol) and B(C6F5)3 (3 mol%) was stirred at
r.t. for the time given in Table 1. After completion of the reaction,
H2O (10 mL) was added to the reaction mixture, which was extract-
ed with EtOAc (3 × 10 mL). The combined organic layers were
washed with brine (10 mL), dried (Na2SO4), filtered, concentrated
and purified by column chromatography (EtOAc–hexanes, 1:1 to
4f
White solid; mp 198–200 °C.
IR (neat): 2924, 2853, 1639, 1507, 1380, 1237 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.28–6.98 (m, 4 H), 4.34–4.26 (m,
1 H), 2.48–1.75 (m, 12 H), 1.44–0.78 (m, 11 H).
4:1). The products obtained were characterized by IR, 1H NMR, 13
C
NMR and mass spectroscopy; spectroscopic data for the new prod-
ucts are listed.
13C NMR (75MHz, CDCl3): d = 196.7, 152.5, 135.4, 131.5, 131.1,
129.0, 115.7, 36.2, 33.9, 32.1, 29.5, 28.5, 26.0, 24.9, 21.2, 14.1.
HRMS (ESI): m/z calcd for C24H28NO2FNa: 404.2001; found:
404.1997.
4a
White solid; mp 274–276 °C.
IR (neat): 2945, 1636, 1360, 1282, 1229, 1181, 718 cm–1.
4h
Yellow solid; mp 199–200 °C.
1H NMR (200 MHz, CDCl3): d = 7.85–7.01 (m, 10 H), 5.36 (s, 1 H),
2.58–1.57 (m, 12 H).
IR (neat): 2926, 2856, 1639, 1381, 1283, 1240, 1182 cm–1.
13C NMR (75 MHz, CDCl3): d = 196.2, 151.7, 146.6, 139.2, 130.2,
129.5, 128.3, 127.9, 126.0, 115.7, 37.0, 32.1, 28.6, 21.3.
1H NMR (200 MHz, CDCl3): d = 7.58–7.40 (m, 3 H), 7.25–7.08 (m,
2 H), 4.34–4.26 (m, 1 H), 2.48–1.75 (m, 12 H), 1.44–0.78 (m, 11 H).
MS (EI): m/z = 370.2 [M + 1]+, 392.1 [M + 23]+.
13C NMR (75 MHz, CDCl3): d = 196.6, 152.7, 139.2, 129.8, 129.2,
115.2, 96.1, 36.8, 32.0, 29.6, 28.3, 25.8, 24.6, 22.7, 21.3, 14.1.
4b
Yellow solid; mp 270–272 °C.
HRMS (ESI): m/z calcd for C24H29NO2Na: 386.2095; found:
386.2084.
IR (neat): 2940, 1636, 1600, 1567, 1507, 1361, 1283, 1232, 1180,
1133, 708, 548 cm–1.
4i
Yellow solid; mp 186–188 °C.
1H NMR (200 MHz, CDCl3): d = 7.66–7.45 (m, 3 H), 7.43–7.22 (m,
4 H), 6.80 (d, J = 8.8 Hz, 2 H), 5.32 (s, 1 H), 3.76 (s, 3 H), 2.40–1.65
(m, 12 H).
IR (KBr): 2926, 2858, 1640, 1507, 1376, 1283, 1186, 1135 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.37–7.07 (m, 4 H), 4.10 (q,
J = 12.4, 5.87 Hz, 1 H), 2.49–1.72 (m, 12 H), 0.97 (d, J = 6.6 Hz, 3
H).
13C NMR (75 MHz, CDCl3): d = 196.3, 158.0, 151.7, 139.3, 139.1,
130.2, 129.5, 128.9, 116.0, 113.8, 55.4, 36.9, 31.4, 28.6, 21.3.
MS (EI): m/z = 422.2 [M + 23]+.
13C NMR (75 MHz, CDCl3): d = 196.4, 164.1, 160.8, 151.7, 135.2,
135.1, 131.4, 117.2, 31.0, 27.0, 22.9, 21.3.
4c
Brown solid; mp 214–216 °C.
HRMS (ESI): m/z calcd for C20H20NO2FNa: 348.1375; found:
348.1384.
IR (neat): 2926, 1683, 1593, 1360, 1230, 753 cm–1.
Synthesis 2008, No. 11, 1737–1740 © Thieme Stuttgart · New York

1740
4j
S. Chandrasekhar et al.
PAPER
3440. (b) Eynde, J. J. V.; Delfosse, F.; Mayence, A.;
Pale-yellow solid; mp 256–258 °C.
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(c) Anniyappan, M.; Muralidharan, D.; Perumal, P. T.
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IR (neat): 2948, 1637, 1360, 1231, 1182 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.63–7.49 (m, 3 H), 7.43–7.22 (m,
4 H), 6.93 (t, J = 8.8 Hz, 2 H), 5.35 (s, 1 H), 2.40–1.75 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 196.3, 151.8, 142.6, 139.0, 129.9,
129.4, 129.2, 115.2, 36.9, 31.6, 28.4, 21.2.
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410.1538.
4k
White solid; mp 279–281 °C.
Berkelhammer, G. J. Am. Chem. Soc. 1958, 80, 992.
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IR (neat): 3413, 1653, 1025, 1004 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.63–7.41 (m, 3 H), 7.31–7.09 (m,
2 H), 4.23 (s, 1 H), 2.48–1.75 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 200.1, 156.6, 152.5, 132.9, 132.6,
117.6, 41.9, 37.3, 31.5, 25.9.
MS (EI): m/z = 294.1 [M + 1]+.
4l
Yellow solid; mp 262–264 °C.
IR (neat): 3418, 1634, 1034, 994 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.63–8.20 (br s, 1 H), 4.16–4.01
(m, 1 H), 2.88–1.80 (m, 12 H), 1.58–1.13 (m, 2 H), 0.69 (t, J = 5.8
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 196.7, 153.1, 113.7, 37.0, 28.0,
27.8, 27.6, 21.4, 9.3.
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MS (EI): m/z = 246.1 [M + 1]+, 268.1 [M + 23]+.
Acknowledgment
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