Acetic acid-promoted eco-friendly one-pot pseudo six-component synthesis of bis-spiro-substituted piperidines

Article abstract of DOI:10.1007/s11164-015-2250-8

A simple, economical, and environmentally benign protocol has been described for one-pot synthesis of 15-(aryl)-3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-1,5,9,13-tetrone by pseudo six-component condensation between formaldehyde, dimedone, and aromatic amine using the dual role of acetic acid as solvent and catalyst at room temperature. Ambient conditions and avoidance of conventional work-up as well as purification procedure qualify this economical and cost-effective protocol for "green synthesis". High efficiency, inexpensiveness, and non-toxicity are the interesting features of this methodology, which make it eco-friendly and highly attractive. One of the important and interesting advantages of this methodology compared to previous methods is that electron-withdrawing substituent anilines also give the desired product which was not possible using the methodologies of Kozlov and Mukhopadhyay.

Full text of DOI:10.1007/s11164-015-2250-8

Res Chem Intermed
DOI 10.1007/s11164-015-2250-8
Acetic acid-promoted eco-friendly one-pot pseudo six-
component synthesis of bis-spiro-substituted piperidines
1
,2
3
•
Mir Rasul Mousavi
Malek Taher Maghsoodlou
•
Hadigheh Gharari
1
1
•
Nourallah Hazeri
Received: 15 July 2015 / Accepted: 28 August 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract A simple, economical, and environmentally benign protocol has been descri-
bed for one-pot synthesis of 15-(aryl)-3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hex-
adecane-1,5,9,13-tetrone by pseudo six-component condensation between formaldehyde,
dimedone, and aromatic amine using the dual role of acetic acid as solvent and catalyst at
room temperature. Ambient conditions and avoidance of conventional work-up as well as
purification procedure qualify this economical and cost-effective protocol for ‘‘green syn-
thesis’’. High efficiency, inexpensiveness, and non-toxicity are the interesting features of
this methodology, which make it eco-friendly and highly attractive. One of the important
and interesting advantages of this methodology compared to previous methods is that
electron-withdrawing substituent anilines also give the desired product which was not
possible using the methodologies of Kozlov and Mukhopadhyay.
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2250-8)
contains supplementary material, which is available to authorized users.
&
Mir Rasul Mousavi
mousavi_5967@yahoo.com
1
Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan,
P.O. Box 98135-674, Zahedan, Iran
2
3
Faculty of Science, Payame Nour University of Khoy, Khoy, Iran
Sina 24 Hour Clinic, Marand, Iran
123

M. R. Mousavi et al.
Graphical abstract
Simple filtration
No need to further purification
R
R
Stirring, 5-10 h
NH2
CH O
CH O
2
2
O
N
O
O
O
O
One-pot
Acetic acid
medium
O
CH O
2
O
O
Room temperature
R:H, CH , NO , Br,...
3
2
No need to column chromatography
Keywords Six-component reaction Á Bis-spiro substituted piperdine Á Acetic acid Á
One-pot Á Green synthesis
Introduction
To produce elaborate, biologically active compounds, multi-component reactions
(
MCRs) have been designed and they have become an important area of research in
organic, medicinal, and combinatorial chemistry [1]. MCRs are a promising and
vital field of chemistry both for academia and industry due to MCRs being rapid,
efficient and time saving, exhibiting intrinsic atom-economy, and enabling the
synthesis of complicated molecules without the isolation of any intermediate. By
expending minimum effort, it minimizes the environmental loading and, regarding
green chemistry, it is satisfactory [2–6]. Therefore, the successful works of
combinatorial chemistry in the process of drug discovery considerably depends on
more advances in the heterocyclic MCR methodology and also the eco-friendly
multi-component procedures [7]. Piperdine as a heterocycle compound has attracted
remarkable interest in recent years. Its derivatives have been known to display a
wide range of pharmacological activities. The piperdine nucleus is a well-known
heterocyclic component in a variety of natural products and medicinal agents.
Compounds bearing the piperidine moiety show anti-hypertensive, antimyco-
bacterial, anticonvulstant, anti-inflammatory, antimalarial, antimicrobial and anti-
HIV activities [8–12]. Also, piperidines have been identified as an important class of
therapeutic agents in the treatment of cancer metastatis, influenza infection,
Alzheimer’s, viral infections (e.g., AIDS), schizophrenia and diabetes [7, 13–17]. In
addition, the piperidine ring is an ubiquitous structural feature of many natural
alkaloid products and drug candidates. As such, Watson et al. [18] asserted that
there were many piperidine compounds mentioned in clinical and pre-clinical
1
23

Acetic acid-promoted eco-friendly one-pot pseudo six-component…
studies. From the importance of piperidine derivatives, are spiro-piperidines, which
are somewhat less prominent. The first spiran described as a bicyclic hydrocarbon
connected by a single carbon was created by Bayer in 1900. For describing the
family of such a hydrocarbon, the spirocyclanes term was used [4]. The ring planes
are nearly perpendicular to each other because of the tetrahedral nature of the spiro-
linked carbon [19]. Spiro compounds have cyclic structures fused at a central carbon
and, due to their interesting conformational features and their structural implications
on biological systems, have gained further interest in recent years [4]. Among them,
the spiro-piperidine system is the core structure of many natural alkaloids and
pharmacological agents. As a consequence, a number of methods have been
reported for the preparation of spiro-piperidines [20–24]. Spiro-piperdine deriva-
tives have an important role in biologically active compounds and, so, show an
interesting template for medicinal chemistry. Due to their useful pharmacological
and biological properties, they have been utilized as medicinal intermediates. Many
of those compounds have been introduced as antidepressants [20], 5-HT1A receptor
and anxiolytic [21], CCR5 antagonist [1], 5-HT2B receptor antagonist [23],
antitumor [6], non-peptide neurokinin-1 (NK1) receptor antagonist [24], inhibitor
in nitric oxide synthase [25], antimycobacterial [26], nicotinic receptor antagonist
[
27], and MCH-1R antagonist [28]. Furthermore, some of the spiro-piperidines have
been used for many years as inhibitors of the influenza A virus M2 protein (AM2) in
the prophylaxis and treatment of influenza A infections [23, 27] (Fig. 1).
To reduce the environmental impact resulting from the use of toxic solvents in
chemical production, the identification and use of ‘‘green’’ solvents is a top priority.
R
N
O
S
O
O
O
N
N
Ar
R
R
R= H, CH ,...
3
Analgetic and anticonvulsant agent
Cl
Antidespressant agent
MeO
H
N
N
F
O
N
H
Cl
N
H
H N
N
2
c-Met/ALK inhibitor
NK1 receptor antagonist
Fig. 1 Biological and pharmacological activity of products containing a spiro-substituted piperdine
moiety
123

M. R. Mousavi et al.
R
O
NH2
O
N
O
AcOH (5 mL)
R.t, 5-10 h
1
3 CH O
2
2
R
O
O
O
1
2
3
4a-i
Scheme 1 Metal-free synthesis of bis-spiro-substituted piperidines using acetic acid
Recently, acetic acid has gained importance as an organocatalyst and versatile
catalyst for effecting various organic transformations, such as the synthesis of poly-
substituted piperidines [29, 30]. To the best of our knowledge, there has been no
attempt to use acetic acid as a catalyst for the synthesis of spiro-piperidines,
particularly
15-(aryl)-3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-
,5,9,13-tetrones [31–33]. There are only three references for synthesizing
5-(aryl)-3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-1,5,9,13-tetrone
1
1
derivatives, considering the above reports, and as part of our work aimed at
developing new methodologies for preparing heterocyclic and new compounds [28,
3
3
4–40], we, therefore, present an efficient and practical synthesis of 15-(aryl)-
,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-1,5,9,13-tetrones from the
corresponding anilines, formaldehyde and dimedone using acetic acid as the solvent
and catalyst at room temperature (Scheme 1).
Results and discussion
First, to achieve suitable conditions for the synthesis of 15-(aryl)-3,3,11,11-
tetramethyl-15-azadispiro[5.1.5.3]hexadecane-1,5,9,13-tetrones 4, we carried out
the one-pot, three(in situ six)-component reaction of 3-nitro aniline 1c, formalde-
hyde 2, and dimedone 3 as a model reaction in different solvents in the presence of
various available catalysts. The results are displayed in Table 1. Different solvents
in the presence of acetic acid as an inexpensive, green and available catalyst and
various Lewis acids were screened in the model reaction. As can be seen from
Table 1, acetic acid is our choice as solvent and catalyst for the reaction, and the
desired product was obtained in excellent yield and high purity (entry 13), while
without any catalyst and; Also, in the presence of some Lewis acids, such as
NiCl Á6H O, La(NO ) Á6H O and Zr(NO ) , the reaction did not progress even after
2
2
3 3
2
3 2
4
8 h. Furthermore, as is evident from Table 1, under solvent-free and catalyst-free
conditions, there was no yield of product, probably due to the absence of strong
interactions between the various reactants (entry 1).
Encouraged by the remarkable results obtained for the above conditions, to
explore the scope and importance of this six-component reaction under optimized
conditions, various aromatic amines including electron-donating and electron-
1
23

Acetic acid-promoted eco-friendly one-pot pseudo six-component…
123

M. R. Mousavi et al.
1
23

Acetic acid-promoted eco-friendly one-pot pseudo six-component…
withdrawing substituents in the aromatic ring, such as –Me, –OMe, –F, –Cl, –Br and
–
NO , were reacted with formaldehyde and dimedone. The reaction time and
2
percentage of yield for each of the products are shown in Table 2. As shown in
Table 2, both electron-rich and electron-deficient anilines gave 15-(aryl)-3,3,11,11-
tetramethyl-15-azadispiro[5.1.5.3]hexadecane-1,5,9,13-tetrones in good to excellent
yields (Table 2, entries 1–9). It is noteworthy that the reactions were done at room
temperature without any strict protection against moisture and air, which accelerates
the reaction rate.
The structures of known products were identified by comparing the melting
points and the analytical data with those reported for authentic samples. The
structures of compounds 4a–i were deduced from their infrared (IR), proton nuclear
1
13
magnetic resonance ( H NMR), and carbon-13 NMR ( C NMR) spectra, mass
1
spectrometry (MS) and by elemental analysis. For example, the H NMR spectrum
of 4e exhibited two singlets due to the geminal methyl protons at d 1.03 and
O
O
H
O
CH3
H
O
CH3
HO
O
O
O
O
O
O
CH CO H
3 2
CH CO H
3
2
H
H
H
H
O
2
5
7
6
3
HO
OH
H
H
O
O
O
O
O
O
Knoevenagel
H2O
O
7
-
O
O
Michael addition
H
O
8
9
10
CH3
O
O
O
H
O
CH3
O
O
O
O
O
N
O
OH
O
H
H
11
Mannich reaction
5
O
O
O
O
NH
O
H
O
CH
H
H
N
R
R
R
14
13
12
AcOH Intra-molecular Mannich
R
-H2O
O
O
N
O
H C
O H
3
H2N
H
H
O
R
O
O
4
5
1
Scheme 2 Mechanism of the tandem reaction for synthesizing bis-spiro-substituted piperidines
123

M. R. Mousavi et al.
1
.04 ppm, and also a singlet at 2.56 ppm for CH protons. The methylene protons of
2
the COCH moiety in 4e were observed as doublets at d 2.69 (J = 14.0 Hz), 2.87
2
(
J = 14.0 Hz). The methylene protons of the NCH moiety exhibited a singlet at d
2
3
.58 ppm. The aromatic protons resonance was observed as a mixture of doublets
1
3
and triplets at d 7.42–7.75 ppm. The C NMR spectrum of 4e showed 14 distinct
resonances that approve the proposed structure. The mass spectrum of 4e displayed
the molecular ion peak at m/z = 454, which is consistent with the proposed 1:3:2
adduct of 3-nitro aniline, formaldehyde, and dimedone. Therefore, all of the spectral
data were in agreement with the proposed structure.
According to our expectation, the product yield and the reaction time in the
presence of acetic acid were improved. On the other hand, both substituted aniline-
containing electron-releasing and electron-withdrawing substituents gave the
corresponding products in high yields and short reaction times (Table 2).
One of the important and interesting advantages of this methodology compared to
previous methods [31, 32] is that electron-withdrawing substituent anilines also give
the desired product (Table 2, entries 5–9) which was not possible using the
methodologies of Kozlov and Mukhopadhyay [31, 32].
Based on the above results and literature [31], a possible mechanism for the
synthesis of bis-spiro piperidines 4a–i is outlined in Scheme 2. The spiro-
cyclization may proceed as a domino sequence of Knoevenagel, Michael and
double Mannich reactions. At first, the acid catalyst changes formaldehyde 2 into
the convenient electrophile 5 via protonation of the carbonyl group. Also, the acid
catalyst changes dimedone 3 into the enol form 7 as a convenient nucleophile via
protonation of the carbonyl group. Next, the reaction proceeded via Knoevenagel
condensation between the intermediate 5 and enol 7, for the formation of a,b-
unsaturated carbonyl compound 9 upon the loss of the water molecule. In the
following, another molecule of enol 7 attacked as a nucleophile via Michael
addition to a,b-unsaturated carbonyl compound 9 to produce intermediate 10.
Simultaneously, the condensation of another molecule of activated formaldehyde 5
with amine 1 gave the imine intermediate 12 which reacted to activated
intermediate 11 via a Mannich reaction to produce the adduct product 13. Further
reaction of intermediate 13 with another molecule of activated formaldehyde 5
gave iminium ion 14. Finally, intra-molecular cyclization was followed by a
Mannich reaction to afford the expected product 4. Therefore, spiro-cyclization
seems to proceed as a domino sequence of Knoevenagel, Michael and double
Mannich reactions. Therefore, the acidic nature of AcOH here may facilitate both
the enolization steps of the 1,3-diketone and activation of formaldehyde and
imine.
Experimental
General
Melting points of all compounds were obtained on an Electrothermal 9100
1 13
apparatus. H and C NMR spectra of compounds were recorded on a Bruker DRX-
1
23

Acetic acid-promoted eco-friendly one-pot pseudo six-component…
4
00 Avance instrument in dimthyl sulfoxide (DMSO) or deuterated chloroform
CDCl ) at 400 MHz. Elemental analyses for C, H, and N were performed using a
(
3
Heraeus CHN-O-Rapid analyzer. The mass spectra for the new compounds were
recorded on an Agilent Technology (HP) mass spectrometer, operating at an
ionization potential of 70 eV. All reagents were purchased from Merck (Darmas-
tadt, Germany), Acros (Geel, Belgium) and Fluka (Buchs, Switzerland), and used
without further purification.
General procedure for the preparation bis-spiro piperidines (15-(aryl)-
3
,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-1,5,9,13-tetrones
To a stirred solution of formaldehyde (3 mmol) and dimedone (2 mmol) in acetic
acid was added aniline (1 mmol) at room temperature for the stipulated time
mentioned in Table 2. Thin layer chromatography (TLC) was used for monitoring
the progress of the reaction. After completing the reaction, a thick precipitate was
obtained. The solid product was filtered off and washed with acetic acid to obtain
pure product. The pure products were characterized by conventional spectroscopic
methods. Physical and spectral data for the synthesized compounds are represented
below.
1
1
5-(4-Bromo phenyl)-3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-
,5,9,13-tetrone (4d)
-
1
Yellow solid, yield: (98 %); mp 202–204 °C. IR (KBr, mmax/cm ): 2959, 1731,
1
721, 1703, 1689, 1590, 1493, 1249, 1222, 1158, 1078, 825, 662, 516. H NMR
1
(
J = 13.6 Hz, 4H, COCH ), 2.84 (d, J = 13.6 Hz, 4H, COCH ), 3.43 (s, 4H, NCH ),
400 MHz, CDCl ): 1.01(s, 6H, CH ), 1.02 (s, 6H, CH ), 2.50 (s, 2H, CH ), 2.65 (d,
3
3
3
2
2
2
2
7.00 (dd, J = 6.8, 2.4 Hz, 2H, Ar–H), 7.35 (dd, J = 6.8, 2.0 Hz, 2H, Ar–H).
1
1
5-(3-Nitro phenyl)-3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-
,5,9,13-tetrone (4e)
-
1
Yellow solid, yield: (93 %); mp 187–189 °C. IR (KBr, mmax/cm ): 2954, 2927,
1
1
1
727, 1700, 1535, 1343, 1204, 871, 788, 740, 680. H NMR (400 MHz, CDCl ):
3
H NMR (400 MHz, CDCl ): 1.03 (s, 6H, CH ), 1.04 (s, 6H, CH ), 2.56 (s, 2H,
3
3
3
CH ), 2.69 (d, J = 14.0 Hz, 4H, COCH ), 2.87 (d, J = 14.0 Hz, 4H, COCH ),
2
2
2
3
1
.58 (s, 4H, NCH ), 7.42 (t, J = 8.0 Hz, 1H, Ar–H), 7.59 (dd, J = 8.2, 2.0 Hz,
2
1
H, Ar–H), 7.75 (dd, J = 11.8, 2.0 Hz, 2H, Ar–H). C NMR (100 MHz, CDCl3):
3
d 28.3, 28.6, 30.8, 32.1, 51.2, 53.4, 65.3, 110.9, 115.5, 124.8, 129.9, 149.0, 151.7,
?
05.8. MS (EI, 70 eV) m/z (%): 454 (M , 14), 426 (20), 398 (2), 370 (76), 341
2
(
12), 313 (11), 285 (39), 257 (10), 218 (12), 178 (21), 150 (100), 121 (10), 83
43), 55 (38). Anal. Calcd for C H N O : C, 66.06; H, 6.65; N, 6.16. Found: C,
(
2
5 30 2 6
6
6.11; H, 6.71; N, 6.21.
123

M. R. Mousavi et al.
1
1
5-(4-Chloro phenyl)-3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-
,5,9,13-tetrone (4f)
-
1
White solid, yield: (75 %); mp 216–218 °C. IR (KBr, mmax/cm ): 2961, 2924,
2
1
2
869, 2836, 2791, 1722, 1732, 1703, 1690, 1595, 1495, 1461, 1422, 1336, 1248,
1
223 1159, 1067, 826, 679, 518. H NMR (400 MHz, CDCl ): d 1.02 (s, 12H, CH ),
3
3
.51 (s, 2H, CH ), 2.66 (d, J = 14.0 Hz, 4H, COCH ), 2.85 (d, J = 13.6 Hz, 4H,
2
2
COCH ), 3.43 (s, 4H, NCH ), 7.05 (d, J = 8.4 Hz, 2H, Ar–H), 7.22 (d, J = 8.4 Hz,
2
2
1
3
2
H, Ar–H). C NMR (100 MHz, CDCl ): d 28.3, 28.6, 30.8, 32.1, 51.2, 54.8, 65.5,
3
?
20.1, 126.6, 129.0, 150.1, 205.9. MS (EI, 70 eV) m/z (%): 443 (M , 21), 415 (3),
1
3
59 (29), 330 (5), 302 (5), 274 (14), 248 (5), 207 (9), 178 (9), 139 (100), 111 (10),
3 (26), 55 (42). Anal. Calcd for C H ClNO : C, 67.63; H, 6.81; N, 3.15. Found:
C, 67.70; H, 6.85; N, 3.20.
8
2
5
30
4
1
1
5-(3,4-Dichloro phenyl)-3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-
,5,9,13-tetrone (4g)
-
1
White solid, yield: (97 %); mp 238–240 °C. IR (KBr, mmax/cm ): 2960, 2948,
1
927, 1734, 1722, 1705, 1691, 1585, 1477, 1251, 1221, 997, 799, 671. H NMR
2
(
400 MHz, CDCl ): 1.02 (s, 12H, CH ), 2.51 (s, 2H, CH ), 2.66 (d, J = 13.6 Hz,
3
3
2
4H, COCH ), 2.85 (d, J = 14.0 Hz, 4H, COCH ), 3.44 (s, 4H, NCH ), 7.02 (dd,
2 2 2
J = 8.8, 2.8 Hz, 1H, Ar–H), 7.13 (d, J = 2.8 Hz, 1H, Ar–H), 7.30 (d, J = 8.8, Hz,
1
3
1
1
1
H, Ar–H). C NMR (100 MHz, CDCl ): d 28.3, 28.6, 30.8, 32.1, 51.2, 54.2, 65.3,
3
?
18.4, 119.7, 124.3, 130.6, 132.6, 150.8, 205.7. MS (EI, 70 eV) m/z (%): 447 (M -
, 21), 431 (2), 393 (38), 364 (5), 336 (6), 308 (17), 266 (9), 241 (10), 207 (5), 173
(100), 137 (11), 97 (14), 69 (48), 41 (25). Anal. Calcd for C H Cl NO : C, 62.76;
25 29 2 4
H, 6.11; N, 2.93. Found: C, 66.83; H, 6.18; N, 2.97.
1
1
5-(4-Nitro phenyl)-3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-
,5,9,13-tetrone (4 h)
-
1
Yellow solid, yield: (92 %); mp 222–224 °C. IR (KBr, mmax/cm ): 2959, 2930,
1
871, 1729, 1700, 1594, 1497, 1327, 1281, 1222, 1110, 947, 826, 753, 665, 500. H
2
NMR (400 MHz, DMSO): 0.92 (s, 6H, CH ), 0.94 (s, 6H, CH ), 2.61 (s, 2H, CH ),
3
3
2
2
4
.75 (d, J = 13.6 Hz, 4H, COCH ), 2.85 (d, J = 13.6 Hz, 4H, COCH ), 3.83 (s,
2 2
1
3
H, NCH ), 7.22 (d, J = 9.6 Hz, 2H, Ar–H), 8.03 (d, J = 9.6 Hz, 2H, Ar–H).
2
C
NMR (100 MHz, DMSO): d 27.9, 28.3, 31.0, 32.2, 49.2, 50.9, 64.9, 113.4, 125.8,
137.0, 153.9, 206.9. Anal. Calcd for C H N O : C, 66.06; H, 6.65; N, 6.16.
25 30 2 6
Found: C, 66.11; H, 6.73; N, 6.22.
1
1
5-(4-Fluoro phenyl)-3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-
,5,9,13-tetrone (4i)
-
1
Yellow solid, yield: (90 %); mp 142–144 °C. IR (KBr, m /cm ):2982, 2924,
max
1
698, 1598, 1508, 1459, 1383, 1238, 1094, 934, 633, 458. H NMR (400 MHz,
1
DMSO): 0.96 (s, 6H, CH ), 1.00 (s, 6H, CH ), 2.04 (s, 2H, CH ), 2.73 (s, 4H,
3
3
2
1
23

Acetic acid-promoted eco-friendly one-pot pseudo six-component…
1
3
COCH ), 2.82 (s, 4H, COCH ), 3.35 (s, 4H, NCH ), 7.28–7.37 (m, 4H, Ar–H).
2
C
2
2
1
NMR (100 MHz, DMSO): d 28.2, 31.2, 32.7, 50.6, 61.6, 116.8 (d, J = 22.5 Hz),
CF
1
28.2, 130.1, 141.5, 148.0, 156.7, 164.9, 188.2, 192.8, 206.9. MS (EI, 70 eV) m/z
?
%): 447 (M -1, 30), 397 (78), 370 (63), 341 (92), 312 (89), 285 (70), 243 (22), 220
(
(
C, 70.24; H, 7.07; N, 2.28. Found: C, 70.32; H, 7.10; N, 2.35.
22), 179 (34), 150 (61), 109 (32), 83 (94), 55 (100). Anal. Calcd for C H FNO :
2
5
30
4
Conclusion
In summary, we have demonstrated a simple, economical, and environmentally
benign protocol for the synthesis of 15-(aryl)-3,3,11,11-tetramethyl-15-
azadispiro[5.1.5.3]hexadecane-1,5,9,13-tetrones at ambient temperature. This pro-
cedure proceeded via a one-pot, six-component reaction between aromatic amines 1,
formaldehyde 2 and dimedone 3 in acetic acid as solvent and catalyst. Some of the
main advantages of this method are ready availability of the starting materials, fairly
high yields of the products, the simplicity of the reaction and mild conditions. The
present method was performed under neutral conditions and required no prior
activation.
Acknowledgments The University of Sistan and Baluchestan is thanked for supporting this work.
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