One-pot DBU-promoted synthesis of hydroacridinones and spirohexahydropyrimidines

Article abstract of DOI:10.1055/s-0033-1339922

The potential hydroacridinone synthesis using simple and inexpensive starting materials, namely 1,3-dicarbonyl compounds, anilines, formaldehyde and DBU as a stoichiometric base was explored. As a result, from the reaction of 1,3-cyclohexanedione and dimedone tetrahydroacridinones were the main reaction products along with small yields of their oxidation products, the dihydroacridinones, whereas in the case of 2-acetylcyclohexanone spirohexahydropyrimidines were isolated in very good yields. Plausible mechanistic schemes for the formation of all products are proposed. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339922

2768▌
LETTER
letter
One-Pot DBU-Promoted Synthesis of Hydroacridinones and Spirohexahydro-
pyrimidines
Synthesis of Hydroacridinones and Spirohexahydropyrimidines
Constantinos G. Neochoritis,1 Nicolaos Eleftheriadis,2 Arianna Tsiantou, Julia Stephanidou-Stephanatou,*
Constantinos A. Tsoleridis*
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
Fax +30(231)0997679; E-mail: ioulia@chem.auth.gr; E-mail: tsolerid@chem.auth.gr
Received: 21.08.2013; Accepted after revision: 09.09.2013
NH2
NH2 OH
Abstract: The potential hydroacridinone synthesis using simple
and inexpensive starting materials, namely 1,3-dicarbonyl com-
pounds, anilines, formaldehyde and DBU as a stoichiometric base
was explored. As a result, from the reaction of 1,3-cyclohexanedi-
one and dimedone tetrahydroacridinones were the main reaction
products along with small yields of their oxidation products, the di-
hydroacridinones, whereas in the case of 2-acetylcyclohexanone
spirohexahydropyrimidines were isolated in very good yields. Plau-
sible mechanistic schemes for the formation of all products are pro-
posed.
N
N
velnacrine
tacrine
Ms
NH
MeO
HN
Bn
NH OH
Key words: acridinones, aza-annulation, DBU as catalyst, 1,3-di-
ones, spiropyrimidines
N
N
suronacrine
amsacrine
Figure 1 Selected examples of bioactive acridine derivatives
The vast majority of nature’s molecules including pro-
teins, nucleic acids and most biologically active com-
pounds contain nitrogen. Consequently, developing new
synthetic methods for the construction of nitrogenous
molecules has defined the frontiers of organic synthesis
since its very beginning.3 Among them, acridine and its
derivatives play an important role in medicinal chemistry.
For example, tacrine is not only a well-known acridine
drug, for the treatment of Alzheimer’s disease4 (AD) but
also useful for the treatment of the central anticholinergic
syndrome.5 Velnacrine and suronacrine, structurally sim-
ilar to tacrine (Figure 1), inhibit acetyl cholinesterase in
vitro and are active in a model that may be predictive of
AD, but have less acute toxicity in rats and mice.6 Amsa-
crine is one of the first DNA-intercalating agents to be
considered as a topoisomerase II inhibitor.7 In addition,
acridine derivatives display a wide range of antiviral,8 an-
tihelminthic,9 and antitumor10 activities. Moreover, acri-
dine and acridinone are chemical families with derivatives
demonstrating strong antimalarial activity.11,12
Among the various methods for the synthesis of such mol-
ecules, the initial step of a Knoevenagel condensation be-
tween 1,3-cyclohexanediones and aldehydes followed by
reaction with an aniline would be a method of choice. In-
deed, the method has been followed by using mainly het-
erocyclic amines leading to the synthesis of pyrazolo and
triazolo heterocycles,15 and also podophyllotoxin16 deriv-
atives. Naphthylamine and 6-aminoquinoline are also re-
ported to follow an analogous reaction pathway leading to
the isolation of phenanthroline derivatives.17 In addition,
recently the reaction between dimedone, aryl aldehydes
and naphthylamine was reinvestigated by using L-proline,
as an organocatalyst, whereupon tetrahydrobenzoacridi-
nones were isolated.18 To the contrary, from the reaction
between anilines, formaldehyde and cyclic β-diketones
3,5-dispiropiperidines were isolated19 in good yields, also
when either homogeneous [FeCl3, In(OTf)3] or heteroge-
neous (silica tungstic acid) catalysts were used,20 whereas
formation of acridinones was not reported. When the
same reaction was repeated in glycerol at 100 °C for two
hours phenylaminocyclohexenyl cyclohexenones were
formed through a Hantzsch reaction.21 These results
prompted us to re-examine the reaction between cyclic
1,3-diones, formaldehyde, and substituted anilines using
DBU as a stoichiometric base reaction promoter, in an at-
tempt to force the reaction to follow a pathway leading to
the formation of hydroacridinones, since as it has been al-
ready mentioned that no systematic study leading to their
synthesis has been reported.
Concerning the synthesis of 1-acridinone derivatives no
systematic study has been described, although some re-
ports referring to the synthesis of 3,4-dihydro-1(2H)-ac-
ridinone or its 3,3-dimethyl derivative can be found in the
literature,13 using as starting materials either 2-amino- or
2-bromo-substituted aryl aldehydes and 1,3-cyclohexane-
diones. In addition, a microwave-assisted synthesis of
some 9-aryl-3,3-dimethylhexahydro-1-acridinones has
been reported.14
SYNLETT 2013, 24, 2768–2772
Advanced online publication: 05.11.2013
DOI: 10.1055/s-0033-1339922; Art ID: ST-2013-B0806-L
© Georg Thieme Verlag Stuttgart · New York
Our initial studies were conducted with dimedone, form-
aldehyde and p-anisidine (2c) as follows: a mixture of p-
anisidine (1 equiv), formaldehyde (9 equiv, 36% aqueous
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Synthesis of Hydroacridinones and Spirohexahydropyrimidines
2769
solution), dimedone (1 equiv) and DBU (1 equiv) in etha-
nol (20 mL) was refluxed for 10 minutes to dissolve all the
reactants and then the reaction mixture was stirred at room
temperature for three hours (Scheme 1). The product,
which was isolated after purification on column chroma-
tography, was identified as acridinone 3g. This result
prompted us to examine the generality of the reaction and
the results summarized in Table 1 show that the reaction
has a broad applicability. Indeed, by following the same
experimental procedure, acridinones 3 were isolated from
all studied reactions in good yields (55–73%, Table 1).
Sometimes, small amounts (5–10%) of their air-oxidized
derivatives, namely the dihydroacridinones 4, were also
isolated. In all cases compounds 3 could be easily oxi-
dized quantitatively to the dihydro derivatives 4 with p-
benzoquinone. All compounds 3 and 4 are novel with the
exception of compounds 4a and 4f, which were prepared
from 2-amino- or 2-bromo-substituted aryl aldehydes and
1,3-cyclohexanediones.13
Table 2 Investigation of Base-Promoted Mannich-Type Reaction
Conditions on 2-Acetylcyclohexanone leading to the Formation of
Spirohexahydropyrimidines 12
Entry
Amine
Catalyst
Yield (%)
1
2
3
4
5
6
2c
2c
2c
2a
2b
2d
DBU
12c (79)
12c (77)
–
K2CO3
DABCO
DBU
12a (68)
12b (70)
12d (61)
DBU
DBU
A possible mechanism for the formation of the acridinone
system is outlined in Scheme 3. Initially, the DBU-cata-
lyzed Knoevenagel condensation leads to the formation of
adduct 7, which suffers a nucleophilic addition of the an-
iline to one of the carbonyl carbons. Most probably, the
abstraction of the labile hydroxyl group of intermediate 8
is the driving force for the facile cyclization reaction with-
out any dismutation reaction.
Table 1 Reactions of Cyclohexane-1,3-diones with p-Substituted
Anilines and Aqueous Formaldehyde22
Entry
R1
R2
R3
Product (%)
Thus, after water elimination, the intermediate imine ad-
duct 9 undergoes an electrocyclic ring closure to interme-
diate 10, and through hydrogen shift and aromatization of
one ring compound 3 is formed. Finally, air oxidation of
3 leads through aromatization of one more ring to the
more stable core of dihydroacridinone 4.
1
2
H
H
H
H
H
H
H
H
H
H
H
Me
3a (69)
3b (70)
3c (73)
3d (65)
3e (70)
3f (73)
3g (69)
3h 61)
3i (55)
3j (62)
4a (–)
4b (4)
4c (6)
4d (–)
4e (–
H
Me
OMe
Cl
3
H
4
H
Next, in continuation of the above studies an analogous
DBU-promoted reaction was conducted with 2-acetylcy-
clohexanone (11), formaldehyde and p-anisidine (Scheme
4). The product, which was isolated after purification on
column chromatography, was identified as 2,4-bis(4-
methoxyphenyl)-2,4-diazaspiro[5.5] undecan-7-one (12c)
in 79% yield. The reaction proceeded analogously afford-
ing 12c in 77% yield, when K2CO3 was used as a base. In
contrast, when 1,4-diazabicyclo[2.2.2]octane (DABCO)
was used, minor amounts of some unidentified products
were formed, whereas in the absence of a base the anilin-
omethylcyclohexanone derivative 13c was isolated.
These results prompted us to use other amines (Table 2)
and in all cases, the corresponding spirohexahydropyrim-
idines 12 were isolated as the only reaction products in
very good yields (61–79%). It is noteworthy that the for-
mation of the same spirohexahydropyrimidines 12 via
proline-catalyzed condensation of cyclohexanone with
anilines and aqueous formaldehyde has been reported.23
Moreover, recently we have studied the acid-catalyzed re-
action between 2-acetylcyclohexanone, formaldehyde
and anilines, whereupon by a double-Mannich annulation
the azabicyclononanones 14 were isolated24 (Scheme 4).
In this way, it is established that the reaction pathway
greatly depends on the reaction conditions.
5
Me
Me
Me
Me
Me
Me
H
6
Me
OMe
Cl
4f (5)
7g (7)
4h (–)
4i (–)
4j (10)
7
8
9
Br
10
Me
Conclusively, as shown in Scheme 2, the reaction between
dimedones, formaldehyde and anilines greatly depends on
the reaction conditions.
R2
O
O
R2
i
CH2O
R1
+
+
R3
R1
R1
N
H
O
R1
R3
R1 R2 R3
NH2
1
3
2
R1 R2
Me Me
R3
O
8
9
1
a H
H
H
H
f
H
R2
9a
oxidation
b H Me
c H OMe H
g Me OMe H
R1
h Me Cl
H
H
4a
10 N
R1
5
4
d H Cl
e Me H
H
H
i
j
Me Br
R3
Me Me Me
4
Concerning a tentative reaction mechanism, it should be
noticed that most probably, due to the lack of a methylene
group between the two carbonyls, the reaction prefers to
follow a different pathway (Scheme 5). Thus, 2-acetylcy-
Scheme 1 DBU-promoted reaction of cyclohexan-1,3-diones with
substituted anilines and formaldehyde. Reagents and conditions: (i)
DBU, EtOH, reflux for 10 min followed by stirring at r.t. for 3 h.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2768–2772

2770
C. G. Neochoritis et al.
LETTER
O
O
R2
R2
[O]
R1
R1
R1
R1
N
N
H
R3
R3
4
3
O
R2
EtOH, reflux, 5 min
then r.t., overnight
ref. 19a
R1
O
R1
FeCl3 (5 mol%)
1
R3
ref. 20a
ref. 20b
ref. 20c
CH2Cl2, r.t.
In(OTf)3 (10 mol%)
CH2O
+
R2
O
N
O
CH2Cl2, r.t., 4–6 h
silica tugstic acid
CH2Cl2, r.t., 4–10 h
R1
R1
R1
R1
O
O
R3
5
NH2
R2
2
R3
R1
R1
R1
R1
NH
HO
ref. 21
O
O
6
Scheme 2 Reaction of cyclohexan-1,3-diones with substituted anilines and formaldehyde under various conditions
clohexanone after initial aminomethylation to the
NOESY
Mannich product 13 is deacetylated by DBU,25 possibly
H
N
H
H
H
H
O
H
O
through intermediate 15 to intermediate 17, which is sub-
jected to a second aminomethylation to give the interme-
diate propane-1,3-diamine 18. Next, subsequent
condensation of 18 with the excess of formaldehyde leads
to the isolated 1,3-diaryl-5-spirohexahydropyrimidine 12.
H
H
H3C
H
H
H3C
H
H
CH3
CH3
CH3
N
CH3
H
H
H
H
H
H
The structural characterization of all compounds 3, 4, and
12 was based on rigorous spectroscopic analysis IR, NMR
(1H, 13C, DEPT, COSY, NOESY, HMQC and HMBC),
mass spectra and elemental analysis data. In Figure 2,
the HMBC correlations between protons and carbons via
2JC–H and 3JC–H in compounds 3f and 4f are depicted.
3f
4f
NOESY
Figure 2 HMBC correlations between protons and carbons via
2JC–H and 3JC–H in compounds 3f and 4f
In conclusion, by using DBU as a base reaction promoter,
we have developed a simple and efficient one-pot conden-
sation of substituted anilines, aqueous formaldehyde and
O
O
O
O
R2
H2C
O
CH2
CH2
O
+
base
••
R1
R1
R1
R1
OH
O
R1
R2
– H2O
R1
N
H
H2N
R3
R1
R1
••
HO
R3
1
7
8
O
O
O
O
H
R2
[O]
R2
CH2
N
R2
H-shift
– H2O
R1
R2
R1
R1
R1
N
N
N
R1
R1
R1
R1
H
R3
R3
R3
R3
10
9
3
4
Scheme 3 Mechanistic rationalization for the formation of acridinones 3 and 4
Synlett 2013, 24, 2768–2772
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Hydroacridinones and Spirohexahydropyrimidines
2771
R
References and Notes
(1) New address: C. G. Neochoritis, Department of Drug
Design, University of Groningen, Groningen, The
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(2) New address: N. Eleftheriadis, Groningen Research Institute
of Pharmacy, University of Groningen, Groningen, The
Netherlands.
O
N
N
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R
Me
12
reflux, 5 min,
then r.t., 3 h
O
O
11
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EtOH
+
CH2O
HN
R
R
or H2O
R
O
O
13
concd HCl (2 drops)
ref. 24
NH2
2
N
a R = H
b R = Me
c R = OMe
d R = Cl
O
O
14
Scheme 4 Reaction of 2-acetylcyclohexanone with substituted ani-
lines and formaldehyde, under various reaction conditions; for bases
used to obtain compounds 12, see Table 2
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1,3-dicarbonyl compounds leading to the synthesis of tet-
rahydro- and dihydroacridinones, belonging to a class of
pharmacologically interesting compounds. Simplicity of
operation, high yields, easy workup and a wide range of
substrate applicability are the key advantages of the meth-
odology. Moreover, it should be pointed out that all of the
previously described methodologies involving condensa-
tion of anilines, aqueous formaldehyde and 1,3-dicarbon-
yl compounds without a base reaction promoter resulted
in the formation of dispiropiperidines. By using 2-acetyl-
cyclohexanone, through an unexpected reaction, spiro-
hexahydropyrimidines were isolated and it is well known
that various natural products and pharmaceutical agents
containing the hexahydropyrimidine moiety exhibit a
broad range of biological activities.26
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N
N
N
N
R
O
O
DBU
Me
CH2OH
Me
CH2NH
15
+
+
Me
– H2O
CH2NH
13
R
R
O
NH2
O
O
O
11
2
Ar
O
N
N
CH O
CH2O
– H2O
2
+
2
N
CH2NH
CH2NH
Ar
Ar
+
– H2O
N
CH2NH
R
O
O
Ar
COMe
16
17
18
12
Scheme 5 Mechanistic rationalization for the formation of spirohexahydropyrimidines 12
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2768–2772

2772
C. G. Neochoritis et al.
LETTER
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small amount of 4f. In an analogous manner, using 2-
acetylcyclohexanone (2.0 mmol) product 10b was isolated.
(a) 3,3,7-Trimethyl-3,4,9,10-tetrahydroacridin-1(2H)-one
(3f): white crystals; mp 230–232 °C; yield: 73%. 1H NMR
(300 MHz, CDCl3): δ = 1.09 (s, 6 H, 2 × Me, 3-Me), 2.236
(s, 2 H, 4-H), 2.245 (s, 3 H, 7-Me), 2.27 (s, 2 H, 2-H), 3.67
(s, 2 H, 9-H), 5.87 (br s, 1 H, NH), 6.50 (d, J = 7.9 Hz, 1 H,
5-H), 6.85 (dd, J = 7.9, 1.7 Hz, 1 H, 6-H), 6.91 (d, J = 1.7
Hz, 1 H, 8-H). 13C NMR (300 MHz, CDCl3): δ = 20.7 (7-
Me), 24.2 (C-9), 28.5 (2 × Me, 3-Me), 32.6 (C-3), 42.4 (C-
4), 50.7 (C-2), 104.3 (C-9a), 114.6 (C-5), 122.8 (C-8a),
127.4 (C-6), 130.5 (C-8), 133.1 (C-7), 134.2 (C-10a), 151.3
(C-4a), 194.8 (C-1). LC–MS (ESI, 1.65 eV): m/z = 242 (100)
[M + H]+. Anal. Calcd for C16H19NO (241.33): C, 79.63; H,
7.94; N, 5.80. Found: C, 79.78; H, 7.78; N, 5.96. (b) 3,3,7-
Trimethyl-3,4-dihydroacridin-1(2H)-one (4f): white
crystals; mp 95–97 °C; yield: 73%. 1H NMR (300 MHz,
CDCl3): δ = 1.15 (s, 6 H, 2 × Me, 3-Me), 2.54 (s, 3 H, 7-Me),
2.64 (s, 2 H, 2-H), 3.18 (s, 2 H, 4-H), 7.62 (dd, J = 8.6, 1.7
Hz, 1 H, 6-H), 7.68 (d, J = 1.7 Hz, 1 H, 8-H), 7.94 (d, J = 8.6
Hz, 1 H, 5-H), 8.73 (s, 1 H, 9-H). 13C NMR (75 MHz,
CDCl3): δ = 21.5 (7-Me), 28.4 (2 × Me, 3-Me), 32.8 (C-3),
47.2 (C-4), 52.6 (C-2), 125.4 (C-9a), 126.9 (C-8a), 128.36
(C-8), 128.42 (C-5), 134.6 (C-6), 135.8 (C-9), 136.7 (C-7),
148.8 (C-10a), 160.0 (C-4a), 198.1 (C-1). LC–MS (ESI, 1.65
eV): m/z = 240 (100) [M + H]+. Anal. Calcd for C16H17NO
(239.31): C, 80.30; H, 7.16; N, 5.85. Found: C, 80.60; H,
7.18; N, 6.05.
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column chromatography on silica gel using petroleum ether–
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Synlett 2013, 24, 2768–2772
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