Novel Cyclic Enaminone Esters and N-Heterocycles by Divergent Chemical Behavior through Amine-Mediated Reactions

Article abstract of DOI:10.1002/hlca.201400376

New acridinones and enaminone esters were synthesized by microwave-assisted tandem-Michael-Michael addition and cyclization from cyclohexane-1,3-diones. The reaction mechanism for both open and closed structures, and the presence of intramolecular twelve-

Full text of DOI:10.1002/hlca.201400376

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Helvetica Chimica Acta – Vol. 98 (2015)
Novel Cyclic Enaminone Esters and N-Heterocycles by Divergent Chemical
Behavior through Amine-Mediated Reactions
by Liliana E. Luna, Walter Tontarelli, Pamela Forastieri, and Raquel M. Cravero*
IQUIR-CONICET (Instituto de Química Rosario), Departamento de Química Orgµnica, Facultad de
Ciencias Bioquímicas y FarmacØuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK,
Rosario, Argentina (phone/fax: þ 54-341-4370477; e-mail: cravero@iquir-conicet.gov.ar)
New acridinones and enaminone esters were synthesized by microwave-assisted tandem-Mi-
chaelÀMichael addition and cyclization from cyclohexane-1,3-diones. The reaction mechanism for both
open and closed structures, and the presence of intramolecular twelve-membered rings derived from NH
and OH H-bonds of enaminone esters are discussed.
Introduction. – Drugs, such as amsacrine and nitracrine, both containing an acridine
ring, have been used for cancer treatment and also considered as models for the
development of new derivatives. The anticancer properties of both structures are
attributed to their ability to insert into the DNA, disrupting cellular processes through
inhibition of topoisomerase II [1][2].
ꢀ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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Acridines and quinolines are also privileged motifs in drug discovery in the field of
neurodegenerative and protozoan diseases. As analogs of huperzine and tacrine, 5-
amino-5,6,7,8-tetrahydroquinolinones have been synthesized and evaluated for their
ability to inhibit cholinesterases, providing effective treatment of Alzheimer and
myasthenia gravis [3][4].
The 9-aminoacridine unit is also found in quinacrine [5], one of the first known
structures used as antimalarial agent. This structure has inspired many scientists to
design, synthesize, and evaluate a variety of related compounds [6 – 8].
In general, acridines are derived from multicomponent reactions of the Hantzsch
type, via conjugate addition between dimedones, amines, and a Knoevenagel product
[9 – 12].
Related N-substituted enaminones are also structures of pharmaceutical interest as
motifs of 1,4-dihydropyridines or pyran-1,3-diones with antitumor, anticancer,
fungicidal, antimalarial, and bactericidal properties [13][14]. In particular, enaminones
without substitution at the C-atom of the CH2(2,2’) groups have been prepared and
described since 1971, along with mono enaminone esters that were synthesized and
evaluated for their anticonvulsant activities [15].
Exploring new synthetic strategies that contribute to structural diversity in
molecules with biological activity, we have synthesized tricyclic ketals based on natural
terpenes, such as quassinoids, alkenes from phenylbutyraldehydes [16][17], and
more recently O-bearing hydroxanthenes, in solution and solid phase [18 – 20].
Currently, we have developed a method aimed at discovering new structures for both
representative compounds, 1,8-dioxoacridines 3 – 5 and enaminone esters 6 – 10, as
shown in Scheme 1.
Results and Discussion. – In this work, we developed tandem-Michael additions
using cyclohexane-1,3-diones 1a and 1b with HCꢀCCOOMe under l-proline catalysis
to give 2a and 2b with assistance of microwave heating, which reduced reaction times
from 13 d to 15 min at 808 in EtOH. It also increased product yield (88 – 91%) when
compared with the procedure using magnetic stirring at room temperature. Once
formation of 2a and 2b was achieved, we planned the cyclization reaction with
AcONH4, BnNH2, or N,N-dimethylpropane-1,3-diamine as source to introduce the N-
atom required for the heterocycle unit (Scheme 1).
Incorporation of the NH group with AcONH4 to bis-dione 2a (R ¼ H) in a
CF3CH2OH solution at 708 during 5.5 h gave 3 in 65% yield. When the same reaction
was carried out with 2b under magnetic stirring or sonication, a mixture of non-
identified products was observed. This outcome shows the difference in dione
reactivity, which translates into the absence or failure in the formation of the
corresponding enaminone.
To fulfill the requirements for the synthetic transformations of the ester/acid series,
we chose to convert crude ester 3 to the parent acid 4 (66% yield) under LiI/AcOEt
conditions.
The more reactive compound 2a could be converted into the N-benzyl tricycle 5 in
70% yield, using BnNH2 by boiling of a solution of 2a in benzene for 14 h. On the
contrary, the reaction of the more substituted compound 2b with AcONH4, N,N-
dimethylpropane-1,3-diamine, or BnNH2 in AcOH or benzene under reflux (ca. 13 h)

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Scheme 1. Synthesis of N-Heterocycles 3 – 5 and Enaminone Esters 6 – 10
did not provide the acridine core. Likewise, other less substituted diones, such as 5-
methyl and 4,4-dimethyl cyclohexanediones, showed low reactivities under different
reaction conditions leading to mixtures of products in very low yields.
Dimedone 1b showed greater reactivity with BnNH2 when compared to cyclo-
hexane-1,3-dione 1a under microwave irradiation. In fact, 2b produced enaminone 8,
although with an associated reaction of N-debenzylation in acidic media [21].
When the reactions of 2a and 2b with N,N-dimethylpropane-1,3-diamine were
performed in benzene under reflux for 8 – 13 h, only the new corresponding products 6
and 9 were obtained after careful chromatography and in moderate yields (52 and 61%,
resp.).
Compound 7 was achieved by the reaction of 2a with BnNH2 in EtOH at 458 for 8 h
as colorless pure oil after two rounds of chromatographic purification in moderate yield
(63%). However, according to the difference in reactivity between 1a and 1b,
microwave assistance was necessary to obtain 10 (73% yield).
The different behavior of 2a and 2b in the amine reactions under diverse reaction
conditions can be explained regarding the keto-enol and iminium-enaminone
tautomerisms involved in the reaction. Therefore, we propose a reaction mechanism
which accounts for both structures with a first step that includes the nucleophilic
addition of the amine (or ammonia) to one of the C¼O groups in 2 to form the
corresponding carbinolamine (Scheme 2). Subsequently, this carbinolamine undergoes
dehydration to give an intermediate implicated in an iminium-enaminone tautomeric
equilibrium. In a second step, if a 1808 rotation occurs, such enaminones (vinylogous

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Scheme 2. Reaction Mechanism Underlying the Formation of Both Structures: Heterocycles 3 – 5 and
Enaminones 6 – 10
amides) produce an intramolecular nucleophilic attack at the C¼O group of the other
dione motif. Then, the subsequent hemiaminal eliminates the OH group by
dehydration to give decahydrodioxoacridines 3 – 5. Likewise, when the open structure
is stabilized by H-bonding, it does neither render heterocycles, nor a lactam generated
by intramolecular reaction between amino and ester groups [22a]. A related reaction
has been described by Dubas-Sluyter et al. between ketones and HCꢀCCOOH to give
1,8-dioxoperhydroacridines [22b]. The NMR spectra of 3 – 5 were similar and showed a
simple pattern of nucleus signals which were related by the plane of symmetry within
these molecules. Products 6 – 10, that were derived from 2 in the presence of l-proline,
were chiral compounds but obtained as mixtures and they showed no net optical
activities. The NMR spectra of 6 – 10 sharing chemical shift patterns were more
complex than those of precursors 2. These spectra showed the H-atoms of the CH2

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group in the ester moiety as diastereotopic. For example, the 1H-NMR spectrum of 7
showed signals at d(H) 14.69 and 9.57 for H-atoms implicated in H-bond interactions.
Aromatic H-atoms appeared in the range between d(H) 7.31 and 7.17, while the CH2
group of the BnNH moiety was detected at 4.46. The CH2 group in the ester moiety
exhibited a set of two doublets of doublets at d(H) 3.24 and 2.90, each one integrating
for one H-atom. A value of J ¼ 16.1 was due to coupling between Ha-atoms while J ¼
6.9 corresponded to coupling with the neighboring H-atom. In the 13C-NMR spectrum
of 7, an increase in the number of signals, in respect to 2, provided evidence that there
was no symmetry in the molecule. In the IR spectra of 6 – 10, the bands of C¼O and NH
groups were characteristic of H-bonded systems (see the Exper. Part).
The GC/MS of 6 showed two peaks: the major one (tR 34.76 min) with m/z
.
58 corresponding to the fragment of the cationic radical Me2HNþCH2 derived from the
iminium species. The smallest peak that appeared at tR 34.27 min corresponded to the
fragment ions of the enaminone species: m/z 94, 108, and 164. This analysis of 6
confirmed the presence of two species in solution, while GC/MS analysis of 7 showed a
single peak at tR 70.25 min, corresponding to the fragmentation of the enaminone
species (m/z 108) towards the cationic BnNHþ3 .
These compounds also show prototropic tautomerism, which is an important
process in many organic transformations. The keto-enol and enamine-imine tautomer-
isms are the subject of research given their importance not only in organic chemistry,
but also in biological processes. In some cases, the tautomerism to a stable enamine is
rare and requires stabilization by extensive delocalization of electrons, forming more
1
complex structures, or H-bonds [23]. In this sense, H-NMR spectra of 6 – 10 showed
two signals displaced at low field, d(H) 9 for NH and another one at 15 for OH, both
involved in H-bonds. Therefore, in comparison with drug-like organic molecules that
interact with their biomolecular targets, we postulate the presence of two H-bonds, with
both donors present in the molecule, that generate a temporary ring system, a situation
that often occurs in a thermodynamic equilibrium between closed and open
conformations (Scheme 3) [24].
The molecular geometries of 7 and 10 were calculated using the MMplus molecular
mechanics method and then optimized with the semiempirical AM1 method at the
UHF level, using HyperChem package software, version 7.01. The Figure shows the
Scheme 3. Proposed Structure with Internal H-Bonds: Thermodynamic Equilibrium between Open and
Closed Conformations

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Figure. Schematic depiction of H-bond interactions of 7 (left) and 10 (right) involving two moieties
minimum energy conformations of 7 and 10 (15.75725 and 17.09042 kcalmolÀ1, resp.),
whose cyclic moieties are held together by two H-bonds. The NÀH ··· O¼C distances
are 2.01 and 2.09 Š with bond angles of ca. 156.78 for 7 and 162.58 for 10, while the
OÀH ··· O¼C distances are 2.19 and 1.97 Š, with bond angles of 168.4 and 159.78,
respectively.
These interactions may be a dominant factor governing the stability of these
vinylogous amides, which do not display the expected reactivities to proceed with the
cyclization to the heterocycle of acridine [24].
The distinct conformations adopted by the product of 2a with BnNH2 in polar and
non-polar environments illustrate the formation of 7 and 5, respectively.
Structures comparable to 6 – 10 were found as intermediates in the synthesis of
9,10-diarylacridine-1,8-diones in ionic liquid [10]. Moreover, these compounds could be
of interest for their very selective interactions bearing a resemblance to the pairing of
bases among portions of purines and pyrimidines in nucleic acids in which the H-atom
of the NH group participates in interactions leading to an arrangement of two eight-
membered cycles [25][26]. Intermolecular interactions involving H-bonds are also
responsible for catalysis and molecular recognition [27].
Conclusions. – In conclusion, the robustness of the tandem-MichaelÀMichael-
cyclization strategy previously developed for syntheses of xanthenediones from
cyclohexane-1,3-diones is now applied to the synthesis of N-heterocycles, decahydro-
1,8-dioxoacridine-9-acetic acid (4), and its methyl esters 3 and 5, and methyl 3-(2-
amino-6-oxocyclohex-1-en-1-yl)-3-(2-hydroxy-6-oxocyclohex-1-en-1-yl)propanoates
6 – 10. Thus, we were able to construct two different types of compounds of prospective
biological interest through a single key precursor that follows different routes
according to amine/solvent combination and reaction conditions.

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Compounds 3 – 5 are appealing structures since they allow subsequent functional-
ization of their side chain and rings. Compounds 6 – 10 structurally display an attractive
array of H-bonds whose multiple cyclic H-atom transfer involves NH and OH donors,
leading to H-bonding arrays of heterocyclic units.
We wish to thank the National Council of Scientific and Technological Research (CONICET) as well
as the National Agency for the Promotion of Science and Technology (ANPCYT) for funding this
research.
Experimental Part
General. All reagents and solvents were used directly as purchased or purified according to standard
procedures. All reactions involving air- or moisture-sensitive materials, were carried out under N2.
Microwave heating was performed in a CEM Discover ꢁ System using septum-sealed 10-ml vials for high-
pressure reaction conditions under stirring and IR-monitored temp. control. Flash column chromatog-
raphy (FC): silica gel (SiO2; 300 – 400 mesh); under slight N2 pressure with increasing gradients of solvent
mixtures. IR Spectra: Shimadzu Prestige-21 spectrophotometer; liquid films in NaCl; n˜ in cmÀ1. 1H- and
13C-NMR spectra: Bruker Avance-300 MHz NMR spectrometer (300.13 and 75.4 MHz, resp.); in CDCl3;
d in ppm rel. to solvent as internal standard, J in Hz. GC/MS: Shimadzu QP-2010 plus spectrometer. HR-
ESI-MS: LC-QTOf Bruker MicroTOF QII; in m/z.
Molecular geometries of 7 and 10 were calculated using the MMplus molecular mechanics method
and then optimized with the semiempirical AM1 method at UHF level using HyperChem version 7.01
software. Enthalpies of formation were obtained by AM1 from single point calculations on the optimized
geometries.
Procedure for the Microwave-Assisted Tandem-MichaelÀMichael Reaction [28]. 1,3-Dione (1 mmol)
dissolved in anh. EtOH (3 ml) was added to an oven-dried 10-ml pressure-rated reaction vial equipped
with a stirring bar. Then, HCꢀCCOOMe (0.088 ml, 1.1 mmol) and l-proline (18 mg, 6 mol-%) were
added. The resulting soln. was stirred at 808 in the microwave reactor until complete conversion of the
dione. After 15 min, the solvent was removed under reduced pressure, and the crude product was
dissolved in AcOEt (3 ml). Finally, NH4Cl (1 ml) was added. The aq. phase was extracted with AcOEt
(2 Â 3 ml), and the org. phase was dried (Na2SO4), filtered, and solvent was removed under reduced
pressure to give 2 in 88 – 91% yield.
Methyl (1,2,3,4,5,6,7,8,9,10-Decahydro-1,8-dioxoacridin-9-yl)acetate (3) [22b]. AcONH4 (45.0 mg,
0.59 mmol) was added to a soln. of 2a (145.0 mg, 0.47 mmol) in CF3CH2OH (3 ml). The mixture was
stirred continuously at 708 until the reaction was completed after 5.5 h. The solvent was removed under
reduced pressure, giving a crude product that was purified by FC producing 3 as pale yellow oil. Yield:
85.0 mg (65%). IR: 3176 (NH), 2946 (CH), 1728 (ester C¼O), 1624 (C¼O), 1382 (CÀN), 1180 (ester
CÀO). 1H-NMR: 6.27 (s, NH); 4.34 (t, J ¼ 5.3, HÀC(9)); 3.57 (s, MeO); 2.49 – 2.27 (complex signal,
CH2(2,4,5,7)); 2.35 (d, J ¼ 5.4, CH2COOMe); 2.07 – 2.01 (complex signal, CH2(3,6)). 13C-NMR: 196.4
(C¼O); 172.6 (ester C¼O); 152.5 (CÀN); 111.9 (¼CÀC¼O); 51.4 (MeO); 39.1 (CH2COOMe); 37.2
(CH2C¼O); 27.3 (CH2C¼CÀC¼O); 26.0 (CHCH2COOMe); 21.2 (CH2CH2C¼O). HR-ESI-MS: 312.1203
([M þ Na]þ, C16H19NNaOþ4 ; calc. 312.1206).
(1,2,3,4,5,6,7,8,9,10-Decahydro-1,8-dioxoacridin-9-yl)acetic Acid (4). LiI (0.24 g, 1.76 mmol) was
added to a soln. of 3 (85 mg, 0.3 mmol) in anh. AcOEt (3 ml). The mixture was heated under reflux
under continuous stirring for 15 h. A second portion of LiI (0.16 g, 1.19 mmol) was added, and the
mixture was heated under reflux for 23 h. The solvent was removed under reduced pressure, giving a
crude oil which was purified by FC producing 4 as pure colorless oil. Yield: 66%. IR: 3358 (OH), 3302
(NH), 2922 (alkane CH), 1730 (acid C¼O), 1620 (C¼O), 1600 (C¼C), 1259 (CÀN), 1180 (CÀO), 1112,
1
1018, 800. H-NMR: 5.37 (s, NH); 4.09 (t, J ¼ 5.2, HÀC(9)); 2.45 – 2.23 (complex signal, CH2(2,4,5,7));
2.10 (br. d, J ¼ 5.3, CH2COOH); 1.96 – 1.85 (complex signal, CH2(3,6)). 13C-NMR: 200.8 (C¼O); 180.1
(COOH); 156.3 (CÀN); 111.6 (¼CÀC¼O); 41.8 (CH2COOH); 36.3 (CH2C¼O); 26.5 (CH2C¼CÀC¼O);
25.3 (CHCH2COOH); 20.4 (CH2CH2C¼O). HR-ESI-MS: 314.0791 ([M þ K]þ, C15H17KNO4þ ; calc.
314.0789).

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Methyl (10-Benzyl-1,2,3,4,5,6,7,8,9,10-decahydro-1,8-dioxoacridin-9-yl)acetate (5). BnNH2 (40.4 mg,
0.38 mmol) was added to a soln. of 2a (104.2 mg, 0.34 mmol) in anh. benzene (10 ml). The mixture was
stirred under reflux for 14 h until the reaction was complete using a flask equipped with a DeanÀStark
trap. The solvent was removed under reduced pressure, giving a crude product that was purified by FC to
give 5 as pure yellow oil fluorescent under UV. Yield: 70%. IR: 2950 (alkane CH), 2360 and 1734 (ester
C¼O), 1630 (C¼O), 1388 (C¼Nþ), 1176 (ester CÀO), 1138. 1H-NMR: 7.33 – 7.16 (m, 5 arom. H); 4.84 (s,
ArCH2); 4.51 (t, J ¼ 5.4, HÀC(9)); 3.56 (s, MeO); 2.62 – 2.22 (complex signal, CH2(2,4,5,7)); 2.36 (d, J ¼
5.3, CH2COOMe); 1.96 – 1.84 (complex signal, CH2(3,6)). 13C-NMR: 196.1 (C¼O); 172.7 (ester C¼O);
154.0 (¼CÀN); 137.0, 129.3, 127.8, 125.1 (arom. C); 114.1 (¼CÀC¼O); 51.3 (MeO); 49.1 (ArCH2); 39.3
(CH2COOMe); 36.4 (CH2C¼O); 26.7 (CH2C¼CÀC¼O); 25.2 (CHCH2COOMe); 21.6 (CH2CH2C¼O).
HR-ESI-MS: 380.1842 ([M þ H]þ, C23H26NOþ4 ; calc. 380.1856).
Methyl 3-(2-Hydroxy-6-oxocyclohex-1-en-1-yl)-3-(2-{[3-(dimethylamino)propyl]amino}-6-oxocy-
clohex-1-en-1-yl)propanoate1) (6). N,N-Dimethylpropane-1,3-diamine (39.8 mg, 0.39 mmol) was added
to a soln. of 2a (100.0 mg, 0.32 mmol) in benzene (10 ml). The mixture was stirred under reflux for 13.5 h
until complete disappearance of the starting material. The solvent was removed under reduced pressure,
giving pure compound 6 as yellow oil after purification by FC. Yield: 52%. IR: 3415 (OH), 3362 (NH),
2943 (alkane CH), 1732 (ester C¼O), 1693 (vinylogous acid C¼O), 1643 (vinylogous amide C¼O in H-
bonding system), 1556 (C¼C), 1265, 1192 (ester CÀO), 1114, 1041. 1H-NMR: 15.03 (s, OH); 9.08 (br. s,
NH); 4.49 (t, J ¼ 7.5, CHCH2COOMe); 3.59 (s, MeO); 3.46 – 3.23 (m, CH2NH); 3.23 (dd, J ¼ 16.9, 7.3,
1 H, CH2COOMe); 3.00 (dd, J ¼ 16.9, 7.3, 1 H, CH2COOMe); 2.72 – 2.14 (complex signal,
CH2(3,3’,5,5’)); 2.37 (m, CH2NMe2); 2.23 (s, Me2N); 1.95 – 1.71 (m, CH2(4,4’)); 1.87 (m, CH2CH2NMe2).
13C-NMR: 200.4 (C(6’)); 193.9 (C(2’)); 180.3 (C(6)); 173.5 (COOMe); 169.8 (C(2)); 116.4 (C(1)); 110.5
(C(1’)); 56.4 (CH2NMe2); 51.3 (MeO); 45.4 (Me2N); 41.9 (CH2NH); 36.3 (C(5’)); 35.7 (CH2COOMe);
35.1 (C(5)); 31.4 (C(3’)); 27.4 (CH2CH2NMe2); 26.7 (CHCH2COOMe); 26.2 (C(3)); 20.5 (C(4’)); 20.2
(C(4)). HR-ESI-MS: 415.2192 ([M þ Na]þ, C21H32N2NaO5þ ; calc. 415.2203).
Methyl 3-[2-(Benzylamino)-6-oxocyclohex-1-en-1-yl]-3-(2-hydroxy-6-oxocyclohex-1-en-1-yl)propa-
noate (7). BnNH2 (30.6 mg, 0.29 mmol) was added to a soln. of 2a (91.0 mg, 0.29 mmol) in EtOH (1 ml).
The mixture was heated, and the temp. was kept between 40 and 508 with continuous magnetic stirring for
8 h until complete disappearance of the reagent. The solvent was removed under reduced pressure, giving
a crude product that was purified by FC to give 7 as colorless oil. Yield: 32.0 mg (63%). IR: 3265 (OH),
3144 (NH), 2947 (alkane CH), 1736 (ester C¼O), 1730 (vinylogous acid C¼O), 1620 (C¼C, NH H-
bonding), 1583 (C¼C coupled with CÀN), 1573 (vinylogous amide C¼O in H-bonding systems), 1433
and 1408 (C¼Nþ conjugated with C¼C), 1306 and 1259 (CÀN free and associated amides), 1199 (CÀO).
1H-NMR: 14.69 (s, OH); 9.57 (s, NH); 7.31 – 7.17 (m, 5 arom. H); 4.55 (t, J ¼ 7.5, CHCH2COOMe); 4.46
(t, J ¼ 6.4, CH2NH); 3.53 (s, MeO); 3.24 (dd, J ¼ 16.1, 6.9, 1 H, CH2COOMe); 2.90 (dd, J ¼ 16.1, 6.9, 1 H,
CH2COOMe); 2.54 – 2.01 (complex signal, CH2(3,3’,5,5’)); 1.86 – 1.54 (complex signal, CH2(4,4’)).
13C-NMR: 200.7 (C(6’)); 195.0 (C(6)); 180.1 (C(2)); 173.4 (COOMe); 169.9 (C(2’)); 137.5, 128.9, 127.5,
126.6 (arom. C); 116.7 (C(1)); 111.1 (C(1’)); 51.4 (MeO); 47.1 (CH2NH); 36.3 (C(5’)); 35.7
(CHCH2COOMe); 35.2 (C(5)); 31.3 (C(3’)); 26.8 (CHCH2COOMe); 26.1 (C(3)); 20.5 (C(4’)); 20.2
(C(4)). HR-ESI-MS: 398.1951 ([M þ H]þ , C23H28NO5þ ; calc. 398.1962).
Methyl 3-(2-Amino-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-3-(2-hydroxy-4,4-dimethyl-6-oxocyclo-
hex-1-en-1-yl)propanoate (8). Crude 2b obtained by microwave-assisted MichaelÀMichael reaction
was dissolved in MeOH/AcOH 9 :1 (10 ml), and BnNH2 (1.06 mmol, 0.12 ml) was added. The mixture
was stirred at 808 in the microwave reactor until complete conversion of 2b. After 15 min, the solvent was
removed under reduced pressure, giving 8 as yellow oil after careful purification along with non-
identified products. Yield: 40%. IR: 3450 (NH H-bonding), 2926 (alkane CH), 1738 (ester C¼O), 1679
(vinylogous acid C¼O in H-bonding system), 1643 (NH H-bonding), 1632 (vinylogous amide C¼O in H-
bonding system), 1613 (C¼C), 1597 (C¼C), 1146 (ester CÀO). 1H-NMR: 9.28 (s, NH); 8.01 (s, OH); 4.34
(t, J ¼ 6.3, CHCH2COOMe); 3.63 (s, MeO); 3.27 (dd, J ¼ 17.0, 7.5, 1 H, CH2COOMe); 3.15 (dd, J ¼ 16.7,
7.6, 1 H, CH2COOMe); 2.70 (s, CH2(3)); 2.40 (s, CH2(3’)); 2.34 (s, CH2(5)); 2.11 (s, CH2(5’)); 1.13, 1.12 (s,
1
)
The C-atoms in the vinylogous acid unit were designated as C(1), C(2), etc., and those in the
vinylogous amide unit as C(1’), etc.

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2 Me); 1.02, 1.01 (s, 2 Me). 13C-NMR: 199.0 (C(6’)); 193.5 (C(6)); 172.8 (COOMe); 165.3 (C(2)); 136.3
(C(2’)); 114.5 (C(1’)); 112.4 (C(1)); 51.1 (MeO); 50.5 (C(5’)); 43.4 (C(5)); 41.4 (C(3’)); 34.7 (C(3)); 32.7
(CH2COOMe); 31.4 (C(4’)); 30.8 (C(4)); 29.7 (Me); 29.0 (Me); 28.6 (Me); 28.2 (Me); 27.1
(CHCH2COOMe). HR-ESI-MS: 386.1668 ([M þ Na]þ, C20H29NNaO5þ ; calc. 386.1938).
Methyl 3-(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-3-(2-{[3-(dimethylamino)propyl]-
amino}-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)propanoate (9). A soln. of dimedone derivative 2b
(103.3 mg, 0.28 mmol) in benzene (10 ml) was added in a flask containing a DeanÀStark trap. N,N-
Dimethylpropane-1,3-diamine (31.8 mg, 0.31 mmol) was added. The mixture was magnetically stirred
under reflux for 8.5 h until complete disappearance of the reagent. The solvent was removed under
reduced pressure, giving the crude product that was subsequently purified by FC to give pure compound 9
as yellow oil. Yield: 58.3 mg (61%). IR: 3474 (OH), 3278 (NH), 2956 (alkane CH), 1733 (ester C¼O),
1688 (vinylogous acid C¼O in H-bonding system), 1640 (NH H-bonding), 1611 (C¼C), 1635 and 1605
(vinylogous amide C¼O in H-bonding system), 1146 (ester CÀO). 1H-NMR: 14.62 (s, OH); 8.75 (br. s,
NH); 4.48 (t, J ¼ 7.6, CHCH2COOMe); 3.53 (s, MeO); 3.41 – 3.20 (m, CH2NH); 3.24 (dd, J ¼ 16.1, 7.3,
1 H, CH2COOMe); 2.97 (dd, J ¼ 16.1, 7.2, 1 H, CH2COOMe); 2.39 – 2.11 (complex signal, CH2(3,3’,5,5’));
2.33 (complex signal, CH2NMe2); 2.20 (s, Me2N); 1.81 (m, CH2CH2NMe2); 1.01 (s, Me); 0.98 (s, Me); 0.94
(s, 2 Me). 13C-NMR: 199.6 (C(6’)); 193.0 (C(6)); 177.9 (C(2’)); 173.4 (COOMe); 167.9 (C(2)); 115.3
(C(1’)); 109.2 (C(1)); 56.5 (CH2NMe2); 51.4 (MeO); 49.9 (C(5’)); 48.6 (C(5)); 45.4 (Me2N); 44.7 (C(3’));
41.9 (CH2NH); 39.5 (C(3)); 35.2 (CH2COOMe); 31.1 (C(4’)); 30.7 (C(4)); 30.3 (Me); 29.9 (Me); 27.4
(CH2CH2NH); 26.3 (CHCH2COOMe); 26.2 (Me). HR-ESI-MS: 449.3010 ([M þ H]þ, C25H41N2O5þ ; calc.
449.3010).
Methyl 3-[2-(Benzylamino)-4,4-dimethyl-6-oxocyclohex-1-en-1-yl]-3-(2-hydroxy-4,4-dimethyl-6-ox-
ocyclohex-1-en-1-yl)propanoate (10). BnNH2 (0.017 ml) was added to a soln. of 2b (50 mg, 0.16 mmol) in
MeOH/AcOH 9 :1. The mixture was stirred at 608 in the microwave reactor until complete conversion of
2b. After 15 min, the solvent was removed under reduced pressure, and the crude product was purified by
FC to give 10 as colorless oil. Yield: 73%. IR: 3271 (OH), 3154 (NH), 2954 (alkane CH), 2830 (MeO),
1735 (ester C¼O), 1662 (C¼C, NH H-bonding), 1581 (C¼C coupled with CÀN), 1408 (C¼Nþ conjugated
with C¼C), 1273 (CÀN free and associated amides), 1165 (CÀO). 1H-NMR: 14.36 (s, OH); 9.32 (s, NH);
7.32 – 7.35 (m, 5 arom. H); 4.65 (t, J ¼ 7.5, CHCH2COOMe); 4.53 (t, J ¼ 5.1, CH2NH); 3.60 (s, MeO); 3.39
(dd, J ¼ 16.1, 6.8, 1 H, CH2COOMe); 2.96 (dd, J ¼ 16.1, 8.4, 1 H, CH2COOMe); 2.38 – 2.30 (complex
signal, CH2(4,4’)); 2.28 (complex signal, CH2(2,2’)). 13C-NMR: 200.0 (C(6’)); 194.3 (C(6)); 177.8 (C(2));
173.4 (COOMe); 168.0 (C(2’)); 137.7, 128.8, 127.5, 126.6 (arom. C); 115.5 (C(1)); 109.9 (C(1’)); 51.5
(MeO); 50.0, 48.8 (C(5,5’)); 47.0 (CH2NH); 44.7 (C(3)); 39.2 (C(3’)); 35.6 (CHCH2COOMe); 31.2
(C(4)); 30.9 (C(4’)); 30.0, 29.6, 26.2, 26.0 (Me); 26.6 (CHCH2COOMe). HR-ESI-MS: 476.2407 ([M þ
Na]þ, C27H35NNaOþ5 ; calc. 476.2407).
REFERENCES
[1] J. R. Goodell, A. V. Ougolkov, H. Hiasa, H. Kaur, R. Remmel, D. D. Billadeau, D. M. Ferguson, J.
Med. Chem. 2008, 51, 179.
[2] M. Gµlvez-Peralta, J. S. Hackbarth, K. S. Flatten, S. H. Kaufmann, H. Hiasa, C. Xing, D. M.
Ferguson, Bioorg. Med. Chem. Lett. 2009, 19, 4459.
[3] Z. Yan, S. Liu, X. Ou, L. Liu, Hecheng Huaxue 2010, 18, 94.
[4] P. R. Carlier, Y.-F. Han, Y.-P. Pang, D.-M. Du, Hong Kong University of Science and Technology, GB
2360518, 2001, US Patent Application Serial No. 09/784,034.
[5] R. Ehsanian, C. Van Waes, S. M. Feller, Cell Commun. Signaling 2011, 9, 13.
[6] J. X. Kelly, M. J. Smilkstein, R. A. Cooper, K. D. Lane, R. A. Johnson, A. Janowsky, R. A. Dodean,
D. J. Hinrichs, R. Winter, M. Riscoe, Antimicrob. Agents Chemother. 2007, 51, 4133.
[7] A. Fernµndez-Calienes ValdØs, Open Med. Chem. J. 2011, 5, 11.
[8] G. Gellerman, S. Waintraub, A. Albeck, V. Gaisin, Eur. J. Org. Chem. 2011, 4176.
[9] C.-S. Yao, C.-H. Wang, B. Jiang, S.-J. Tu, J. Comb. Chem. 2010, 12, 472.
[10] X.-S. Wang, M.-M. Zhang, H. Jiang, D.-Q. Shi, S.-J. Tu, X.-Y. Wei, Z.-M. Zong, Synthesis 2006, 4187.

Helvetica Chimica Acta – Vol. 98 (2015)
1003
[11] G. C. Muscia, G. Y. Buldain, S. E. Asís, Monatsh. Chem. 2009, 140, 1529.
[12] A. Heydari, S. Khaksar, M. Tajbakhsh, H. R. Bijanzadeh, J. Fluorine Chem. 2009, 130, 609.
[13] C. S. Sepffllveda, M. L. Fascio, M. B. Mazzucco, M. L. Docampo Palacios, R. F. Pellón, C. C. García,
N. B. DꢂAccorso, E. B. Damonte, Antiviral Chem. Chemother. 2008, 19, 41.
[14] L. Fang, D. Appenroth, M. Decker, M. Kiehntopf, C. Roegler, T. Deufel, C. Fleck, S. Peng, Y. Zhang,
J. Lehmann, J. Med. Chem. 2008, 51, 713.
[15] I. O. Edafiogho, J. M. Nicholson, K. R. Scott, Howard University, WO1993017678 A1, 1993.
[16] M. F. Plano, G. R. Labadie, B. L. Tekwani, R. M. Cravero, Arkivoc 2011, vii, 477.
[17] M. F. Plano, G. R. Labadie, M. R. Jacob, B. L. Tekwani, R. M. Cravero, Chem. Biodiversity 2011, 8,
1098.
[18] L. E. Luna, G. Seoane, R. M. Cravero, Eur. J. Org. Chem. 2008, 1271.
[19] L. E. Luna, R. M. Cravero, R. Faccio, H. Pardo, . W. Mombrffl, G. Seoane, Eur. J. Org. Chem. 2009,
3052.
[20] R. M. Cravero, L. E. Luna, A. V. Barboza, Synthesis 2011, 4027.
[21] F. Rombouts, D. Franken, C. Martínez-Lamenca, M. Braeken, C. Zavattaro, J. Chen, A. A.
Trabanco, Tetrahedron Lett. 2010, 51, 4815.
[22] a) M. A. T. Sluyter, U. K. Pandit, W. N. Speckamp, H. O. Huisman, Tetrahedron Lett. 1966, 7, 87;
b) M. A. T. Dubas-Sluyter, W. N. Speckamp, H. O. Huisman, Recl. Trav. Chim. Pays-Bas 1972, 91,
157.
[23] J. Cµmpora, S. A. Hudson, E. Carmona, Organometallics 1995, 14, 2151.
[24] B. Kuhn, P. Mohr, M. Stahl, J. Med. Chem. 2010, 53, 2601.
[25] J. L. Huppert, Chem. Soc. Rev. 2008, 37, 1375.
[26] E. B. Cunningham, ꢃBiochemistry: Mechanisms of Metabolismꢂ, McGraw-Hill Book Company, New
York, 1978.
[27] J.-M. Lehn, ꢃSupramolecular Chemistry: Concepts and Perspectivesꢂ, VCH, Weinheim, 1995, p. 191.
[28] V. A. Chebanov, V. E. Saraev, S. M. Desenko, V. N. Chernenko, I. V. Knyazeva, U. Groth, T. N.
Glasnov, C. O. Kappe, J. Org. Chem. 2008, 73, 5110.
Received November 27, 2014