Scandium-catalyzed preparation of cytotoxic 3-functionalized quinolin-2-ones: Regioselective ring enlargement of isatins or imino isatins

Article abstract of DOI:10.1002/cplu.201200090

Trimethylsilyldiazomethane in the presence of catalytic amounts of Sc(OTf)3 smoothly promotes the ring expansion of isatins or imino isatins to efficiently afford 3-functionalized quinolin- 2-ones through controlled ring enlargement. Whereas the ring-expa

Full text of DOI:10.1002/cplu.201200090

DOI: 10.1002/cplu.201200090
Scandium-Catalyzed Preparation of Cytotoxic
3-Functionalized Quinolin-2-ones: Regioselective Ring
Enlargement of Isatins or Imino Isatins
Benito Alcaide,*[a] Pedro Almendros,*[b] Cristina Aragoncillo,[a] Gonzalo Gꢀmez-Campillos,[a]
Manuel Arnꢀ,[c] and Luis R. Domingo[c]
Trimethylsilyldiazomethane in the presence of catalytic
amounts of Sc(OTf)3 smoothly promotes the ring expansion of
isatins or imino isatins to efficiently afford 3-functionalized qui-
nolin-2-ones through controlled ring enlargement. Whereas
the ring-expansion reaction of azetidine-2,3-diones led to the
adduct resulting from migration of the carbonyl group, the
ring-expansion reaction of oxindole derivatives gave the
adduct resulting from migration of the aryl group. To rational-
ize the experimental observations, theoretical studies have
been performed. Moreover, the biological activity of some of
the synthesized heterocycles has been evaluated in four
cancer cell lines.
Introduction
The preparation of nitrogen-containing heterocycles is an im-
portant goal in organic synthesis because of their widespread
occurrence in natural substances and synthetic products of
pharmaceutical interest. In particular, quinolin-2-one deriva-
tives represent a class of important compounds that display
a broad spectrum of biological and chemical functions.[1] The
usual strategies for the preparation of the majority of heterocy-
clic systems start from the appropriate alicyclic precursor,
which after cyclization form the required azacycle. An alterna-
tive strategy involving the preparation of heterocyclic com-
pounds from smaller-sized heterocycles is very appealing.[2]
The ring expansion of cyclic ketones can be effected by reac-
tion with diazoalkanes through methylene insertion.[3] Howev-
er, regioselectivity problems are significant in unsymmetrical
ketones. Following up on our combined interest in the area of
lactams and metal catalysis,[4] herein we report the first scandi-
um-catalyzed synthesis of the relevant quinolin-2-one nucleus
from isatin derivatives, as a convenient alternative to the exist-
ing methods. Moreover, density functional theory (DFT) calcu-
lations were performed to gain insight into the mechanism of
the ring-expansion reaction.
nately, tetramic acid 2a was formed in a totally selective fash-
ion,[6] only the breakage of the C2ꢀC3 bond of the four-mem-
bered ring was feasible (Scheme 1). Because variations in re-
agents and catalysts did not considerably altered results, and
in most cases the reaction failed completely, we decided to
move to isatin derivatives as starting substrates.
At first, we examined the screening of different metallic
chlorides or triflates as catalysts for methylene insertion into
the isatin nucleus. As for the azetidine-2,3-dione case, Sc(OTf)3
Scheme 1. Synthesis of tetramic acid 2a. Reagents and conditions:
1) Sc(OTf)3 (11 mol%), CH2Cl2, 08C, 3 h. PMP=4-CH3OC6H4.
[a] Prof. Dr. B. Alcaide, Dr. C. Aragoncillo, Dipl.-Chem. G. Gꢀmez-Campillos
Departamento de Quꢁmica Orgꢂnica I, Facultad de Quꢁmica
Universidad Complutense de Madrid, 28040 Madrid (Spain)
Fax: (+34)1-3944103
Results and Discussion
E-mail: alcaideb@quim.ucm.es
b-Lactams have been recognized as versatile building blocks in
organic chemistry for the preparation of natural products and
medicinal reagents.[5] With the requirement that metal salts be
the catalytic activation source, we began to address the reac-
tivity of the model system azetidine-2,3-dione 1a with trime-
thylsilyldiazomethane under metal catalysis. Initially, the use of
InCl3 and In(OTf)3 was tested. Next, both Zn(OTf)2 and Cu(OTf)2
were investigated, but all failed to catalyze this reaction. Inter-
estingly, treatment of azetidine-2,3-dione 1a with Sc(OTf)3 in
dichloromethane at 08C gave partial conversion (30%); pyrroli-
dine-2,4-dione 2a was isolated in a poor yield of 21%. Fortu-
[b] Dr. P. Almendros
Instituto de Quꢁmica Orgꢂnica General, IQOG
Consejo Superior de Investigaciones Cientꢁficas, CSIC
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax: (+34)91-5644853
E-mail: Palmendros@iqog.csic.es
[c] Prof. Dr. M. Arnꢀ, Prof. Dr. L. R. Domingo
Departamento de Quꢁmica Orgꢂnica, Universidad de Valencia
C/Dr. Moliner 50, 46100 Burjassot, Valencia (Spain)
Fax: (+34)-96-3543880
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cplu.201200090.
ChemPlusChem 2012, 77, 563 – 569
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
563

B. Alcaide, P. Almendros et al.
was the catalyst of choice. With the optimal reaction condi-
tions in hand, we studied the generality of the ring enlarge-
ment of isatins 3 by reaction with trimethylsilyldiazomethane.
Attempts of a smooth ring-expansion reaction of NH-indoline-
2,3-dione 3a were problematic. 3-Hydroxy-1-methylquinolin-
2(1H)-one 4b, which arises from a selective expansion with
concurrent N-methylation, was obtained in low yield together
with a complicated mixture of by-products. Fortunately, vari-
ous substituted isatin compounds were found to be employa-
ble for the ring enlargement to quinolin-2-ones 4 (Scheme 2).
3-Aminoquinolin-2(1H)-ones are an important subfamily of
quinolin-2-ones showing promising pharmacological proper-
ties,[8] but there is a lack of practical methods for their prepara-
tion in the literature. Therefore, the development of general
and direct routes to 3-aminoquinolin-2-one derivatives is of
great importance for organic and medicinal chemistry. In the
following, we will provide efficient access to these valuable ni-
trogen-containing heteroaromatic scaffolds by applying the
methylene insertion method; showing the ability of the pro-
cess to mediate the same reaction with a second important
class of electrophiles such as imines. Isatin imines 6 derived
from p-anisidine can undergo a clean ring-expansion reaction
by treatment with trimethylsilyldiazomethane under Sc(OTf)3
catalysis. By contrast, the quinolinone formation was not ame-
nable using multiply bonded substrates of the hydrazone type.
As anticipated, the catalytic ring enlargement of imino isatins
shows tolerance to various substituents both at N1 and the
benzenoid ring (Scheme 3). 3-Aminoquinolin-2(1H)-ones
7
Scheme 2. Ring-expansion reaction of indoline-2,3-diones 3a–h to quinolin-
2,3-diones 4b–h and spiro[indoline-3,2’-oxiran]-2-ones 5 f–h. Reagents and
conditions: 1) Sc(OTf)3 (11 mol%), trimethylsilyldiazomethane (2.2 equiv) ,
CH2Cl2, 08C!RT, 3a: 24 h; 3b: 5 h; 3c: 3.5 h; 3d: 24 h; 3e: 2.5 h; 3 f: 3 h;
3g: 5 h; 3h: 2 h.
Scheme 3. Ring-expansion reaction of imino isatins 6a–h to 3-aminoquino-
lin-2(1H)-ones 7a–h. Reagents and conditions: 1) Sc(OTf)3 (11 mol%), trime-
thylsilyldiazomethane (2.2 equiv), CH2Cl2, 08C!RT, 6a: 4 d; 3b: 3 d; 3c: 2 d;
3d: 7 d; 3e: 1 d; 3 f: 7 d; 7g: 3 d; 7h: 3 d.
This transformation tolerates different substituents on the in-
doline-2,3-dione nucleus, such as methyl, aryl, halogen, and
nitro groups. The ring-expansion reaction of isatins with diazo-
alkanes potentially results in the formation of a mixture of re-
gioisomeric products. Interestingly, in contrast to the methyl-
ene insertion reaction of azetidine-2,3-dione 1a which lead to
tetramic acid 2a (adduct resulting from migration of the car-
bonyl group) as the sole product, the reactions of isatins 3
under similar conditions gave 3-hydroxyquinolin-2(1H)-ones 4
(adducts resulting from migration of the aryl group) as the ex-
clusive or major products. Despite the presence of halide sub-
stituents at C5 should provide the same reactivity pattern, the
scandium-catalyzed reaction of 5-haloindolinones 3 f–h with
trimethylsilyldiazomethane, also afforded spiro[indoline-3,2’-
oxiran]-2-ones,[7] 5 f–h as minor, easily separated components
(Scheme 2). Spirocyclic oxiranes 5 arise from methylene inser-
tion into the ketone group. Although complete conversion
were isolated as N-methyl derivatives at the former imine ni-
trogen atom. Although complete conversion was observed by
1
TLC and H NMR analysis of the crude reaction mixtures, some
decomposition was observed for the sensitive fused azacycles
7 during purification by flash chromatography, which may be
responsible for the moderate yields of isolated products. Pleas-
antly, in contrast to their carbonyl counterparts 3 f–h the che-
moselectivity is total for 5-halo-imines 6 f–h, providing the
a-amino lactam ring expansion adducts 7 f–h as sole products
(Scheme 3). Thus, the formation of these quinolinones indi-
cates an important feature, namely, it reveals that the nature
of the multiply bonded group does have an electronic influ-
ence on the course of the ring-expansion process, thus stress-
ing the importance of an imine group to drive the ring expan-
sion towards construction of a 3-substituted quinolin-2(1H)-
one ring.
1
was observed by TLC and H NMR analysis of the crude reac-
The Lewis acid Sc(OTf)3 considerably increases the electro-
philicity of the C=X bond of 3 and 6. Probably, the formation
of 3-substituted quinolin-2(1H)-ones 4 and 7 should proceed
by a pathway that involves approach of the trimethylsilyldiazo-
methyl nucleophile, and subsequent CꢀC bond formation at
tion mixtures, some decomposition was observed on sensitive
quinolones 4 during purification by flash chromatography,
which may be responsible for the moderate yields of isolated
products.
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Homogeneous Catalysis
the 2-indolone stage in the transition state to furnish diazoni-
um salt 8. In the second “event”, species 8 should evolve
through concerted CꢀC breaking bond, associated with ring
expansion and migration of the aryl group with concomitant
loss of a molecule of nitrogen. Intermediate 9 give rise to final
products 4 and 7 after desilylation (Scheme 4).
Scheme 5. Possible pathways for the scandium-catalyzed regioselective rear-
rangement reaction of isatin 3b.
The nitrogen extrusion/ring-expansion processes in the ste-
reoselective ring expansion step via transition structures (TSs)
TS2a and TS2b demand an antiperiplanar rearrangement of
the CꢀN and C2ꢀC3(C4) breaking bonds. Consequently, two in-
termediates, IN1a and IN1b, and the corresponding stereoiso-
meric TSs associated with the nucleophilic attack of trimethylsi-
lyldiazomethane on MC1, TS1a, and TS1b, were studied. Note
that IN1a and IN1b are conformers, being the result of the
C1ꢀC2 bond rotation. The total and relative energies and free
energies are given in Table 1. A comparison of the relative en-
ergies in gas phase and dichloromethane (CH2Cl2) shows that
there are no significant differences. Owing to the different mo-
lecularity involved in the two steps of the reactions, relative
free energies in CH2Cl2 are used in the discussion.
Scheme 4. Mechanistic explanation for the controlled ring-expansion reac-
tions of isatins 3 and imino isatins 6.
Density functional theory (DFT) calculations have been car-
ried out at the B3LYP/6-31G** level to gain more insight into
the reaction mechanism of the above-discussed ring-expansion
reactions of isatins and imino isatins promoted by trimethylsi-
lyldiazomethane under scandium catalysis. For this purpose,
the reaction between Sc(OTf)3·isatin complex MC1 and trime-
thylsilyldiazomethane was chosen as the actual model, as any
molecular simplification could modify the relative energies as-
sociated with the competitive reactive chan-
nels. For the conversion of the isatin structure
into that of quinolinone one demands four dif-
Table 1. Total (E) and relative energies (DE), calculated in gas phase and in dichloromethane,
and total (G, in a.u.) and relative free energies (DG, in kcalmolꢀ1), computed at 258C and
1 atm in dichloromethane, of the stationary points involved in the regioselective scandium-
catalyzed ring expansion of isatin 3b.
ferent chemical processes: 1) electrophilic acti-
vation of the C2 carbonyl carbon atom of
isatin by coordination with Sc(OTf)3 Lewis acid;
2) nucleophilic addition of trimethylsilyldiazo-
methane to the activated carbonyl group;
3) extrusion of a nitrogen-containing molecule;
and 4) a ring expansion of the isatin skeleton
via a 1,2-carbon shift. Owing to the asymmetry
of MC1, several stereoisomeric attack modes
of trimethylsilyldiazomethane on the C2 car-
bonyl carbon atom of MC1 are feasible. For
simplicity, we present here the most favorable
reactive channels associated to the two regio-
selective ring expansions. A schematic repre-
sentation of the two possible pathways is
given in Scheme 5.
Species
Gas phase
Dichloromethane
E
DE
[kcalmolꢀ1
E
DE
G
DG
[kcalmolꢀ1
[a.u.]
]
[a.u.]
[kcalmolꢀ1] [a.u.]
]
MC1
ꢀ4197.607704
–
–
1.6
0.6
ꢀ4197.627004
ꢀ557.432855
ꢀ4755.054491
ꢀ4755.056703
–
–
3.4
2.0
ꢀ4197.470666
ꢀ557.333082
–
–
TMSDZ ꢀ557.429615
TS1a
TS1b
IN1a
IN1b
TS2a
TS2b
ꢀ4755.034736
ꢀ4755.036324
ꢀ4754.774059 18.6
ꢀ4754.773638 18.9
ꢀ4754.786117 11.1
ꢀ4754.781709 13.8
ꢀ4754.778051 16.1
ꢀ4754.768989 21.8
ꢀ4754.869589 ꢀ41.3
ꢀ4754.898388 ꢀ59.4
ꢀ4755.046515 ꢀ5.8
ꢀ4755.042894 ꢀ3.5
ꢀ4755.069944 ꢀ6.3
ꢀ4755.068438 ꢀ5.4
ꢀ4755.034691
ꢀ4755.026702
1.6
6.7
ꢀ4755.058163
ꢀ4755.051945
1.1
5.0
MC2a ꢀ4755.128298 ꢀ57.1
MC2b ꢀ4755.154928 ꢀ73.8
ꢀ4755.146698 ꢀ54.5
ꢀ4755.172390 ꢀ70.6
TMSDZ=Trimethylsilyldiazomethane.
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565

B. Alcaide, P. Almendros et al.
The nucleophilic attacks of trimethylsilyldiazomethane on
MC1 present very low activation energies, 3.4 kcalmolꢀ1 (TS1a)
and 2.0 kcalmolꢀ1 (TS1b). Inclusion of thermal corrections and
entropies, increase the activation free energies to 18.6 and
18.9 kcalmolꢀ1, respectively, as a result of the negative activa-
tion entropy associated with these bimolecular processes.
These low activation barriers are in agreement with the high
electrophilicity of MC1,[9] w=5.07 eV, and the high nucleophi-
licity of trimethylsilyldiazomethane,[10] N=3.32 eV. Note that
coordination of Sc(OTf)3 Lewis acid with isatin increases nota-
bly its electrophilicity, w=2.66 eV. These similar relative free
energies indicate that the first step of the reaction is not ste-
reoselective. Consequently, a mixture of IN1a and IN1b is ob-
tained. Formation of these intermediates is endergonic by 11.1
and 13.8 kcalmolꢀ1, respectively. The energy associated with
the conformer equilibration between IN1a and IN1b, through
a C1ꢀC2 bond rotation, is 6.5 kcalmolꢀ1.
From IN1a and IN1b, the reactive channels associated with
the nitrogen extrusion and the ring expansion to yield MC2a
and MC2b are open. The nitrogen extrusion and the ring
cleavage demand an antiperiplanar rearrangement of the
C1ꢀN and C2ꢀC3(C4) breaking bonds, which is already present
in IN1a and IN1b. The activation free energy associated with
TS2a and TS2b is 5.0 and 8.0 kcalmolꢀ1, respectively. The tri-
methylsilyldiazomethane addition/ring-expansion processes are
strongly exergonic, ꢀ41.3 kcalmolꢀ1 (MC2a) and ꢀ59.4 kcal
molꢀ1 (MC2b). Although the formation of MC2a is less exer-
gonic than the formation of MC2b, the irreversible character
of these reactions, together with the fact that TS2b is located
5.7 kcalmolꢀ1 above TS2a, enables the formation of MC2a by
kinetic control. This energy difference accounts for the com-
plete regioselectivity found in the scandium-catalyzed ring ex-
pansion of isatins.
Figure 1. Geometries of the TSs involved in the scandium-catalyzed ring ex-
pansion of isatin 3b. The distances are given in ꢂ.
nitrogen extrusion/ring-expansion processes take place via
a two-stages, one-step mechanism. In the first stage of the re-
action the nitrogen extrusion occurs, whereas the ring expan-
sion process takes place in the second stage of the reaction
without the participation of any cationic intermediate. A similar
asynchronous ring expansion has been recently observed in
the controlled ring-expansion reactions of 2-indolinone-teth-
ered allenols to quinolin-2,3-diones under bromination condi-
tions.[11]
The geometries of the TSs are given in Figure 1. Along the
nucleophilic attack of trimethylsilyldiazomethane on the C1
carbonyl carbon atom of complex MC1, the length of the
C1ꢀC2 forming bond at the TSs is 2.134 ꢂ at TS1a and 2.095 ꢂ
at TS1b. At intermediates IN1a and IN1b, the length of the
C1ꢀC2 bond is 1.586 and 1.627 ꢂ, respectively. An analysis of
the natural atomic charges at the more favorable IN1a indi-
cates that along the nucleophilic attack of trimethylsilyldiazo-
methane on MC1 some amount of electron density has been
transferred, 0.20e. At the TSs associated with the nitrogen ex-
trusion/ring-expansion process, the lengths of the breaking
bonds are 1.896 (NꢀC1) and 1.531 (C2ꢀC3) ꢂ at TS2a and
1.887 (NꢀC1) and 1.640 (C2ꢀC4) ꢂ at TS2b. The NꢀC1 distan-
ces, which are longer that those at the corresponding inter-
mediate, indicate that the nitrogen extrusion is more advanced
than the CꢀC breaking bond demanded for the ring expan-
sion. At these TSs the N-C1-C2-C3(C4) dihedral angle is ꢀ178.1
(TS2a) and 163.4 (TS2b) degrees. These values, which are
closer to those in the corresponding intermediates, ꢀ179.8
(IN1a) and 164.9 (IN1b) degrees, shown the antiperiplanar re-
arrangement of the NꢀC1 and C2ꢀC3(C4) bonds demanded for
the coupled breaking bonds. In spite of the high asynchronici-
ty in the NꢀC1 and C2ꢀC3(C4) breaking bonds, the intrinsic re-
action coordinate (IRC) from TSs to products confirm that the
From this DFT study, we can conclude: 1) trimethylsilyldiazo-
methane addition/nitrogen extrusion/ring expansion takes
place in two elementary steps via one intermediate; 2) the re-
action takes place with low activation free energy, 18.6 kcal
molꢀ1 (TS1a); 3) owing to the irreversible character of nitrogen
extrusion/ring-expansion process, formation of the final quino-
linone takes place through kinetic control, associated with mi-
gration of the aryl carbon atom via TS2a; 4) the concomitant
nitrogen extrusion/ring expansion demands an antiperiplanar
rearrangement of the C1ꢀN and C2ꢀC3 breaking bonds, which
is persevered along of the reaction pathway; 5) nitrogen extru-
sion/ring expansion processes take place through a highly
asynchronous elementary step.
As the 3-aminoquinolin-2(1H)-one moiety is known to dis-
play biological activity, a biological evaluation of representative
compounds of type 7 was planned (Scheme 6). The cytotoxici-
ty of the mentioned compounds was examined in four differ-
ent cancer cell lines, namely HL-60 (human promyelocytic leu-
kemia), HT-1080 (human fibrosarcoma), HT-29 (human colon
adenocarcinoma), and MDA-MB231 (human breast carcinoma).
The results of this investigation are summarized in Table 2.
Data indicate that best results were obtained with com-
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Homogeneous Catalysis
Conclusion
In conclusion, we have developed a scandium-catalyzed[13]
preparation of 3-hydroxy (or 3-amino) quinolin-2-one deriva-
tives through controlled ring expansion of isatins or imino isa-
tins by reaction with trimethylsilyldiazomethane through meth-
ylene insertion. In addition, both DFT calculations and cytotoxic
studies were performed to obtain insights into the reaction
mechanism and the biological activity, respectively.
Scheme 6. Structure of 3-aminoquinolin-2(1H)-ones 7 used for biological
studies.
Experimental Section
General methods
1H and 13C NMR spectra were recorded on a Bruker AMX-500 or
Bruker Avance-300 instrument. The NMR spectra were recorded in
CDCl3 solutions, except otherwise stated. Chemical shifts are given
in ppm relative to TMS (1 H, 0.0 ppm), or CDCl3 (13C, 76.9 ppm).
Low- and high-resolution mass spectra were measured on an AGI-
LENT 6520 Accurate-Mass QTOF LC/MS spectrometer using the
electronic impact (EI) or electrospray modes (ES) unless otherwise
stated. Specific rotation [a]D is given in 10ꢀ1 degcm2 gꢀ1 at 208C,
and the concentration (c) is expressed in g per 100 mL. All com-
mercially available compounds were used without further purifica-
tion.
Table 2. Antitumor activities IC50 values [mgmLꢀ1] of compounds 7d and
7 f–h in vitro against several cell types.[a]
Entry
Compound
Cell lines[b]
HL-60
HT-1080
HT-29
MDA-MB231
1
2
3
4
5
Cisplatin
7 f
7h
7g
7d
0.49[c]
2.7[d]
5.1[c]
3.7[c]
1.3ꢁ0.2
2.7ꢁ0.3
2.6ꢁ0.3
0.5ꢁ0.1
1.9ꢁ0.1
5.0ꢁ0.6
3.0ꢁ0.4
0.7ꢁ0.1
1.4ꢁ0.1
4.7ꢁ0.5
2.4ꢁ0.1
0.7ꢁ0.1
2.1ꢁ1.0
4.5ꢁ1.9
3.1ꢁ0.9
0.7ꢁ0.4
[a] Cells were incubated for 72 hours in the presence of each compound,
and the ratios of viable cells were determined by MTT assay. The drug
concentration required to inhibit cell growth by 50% (IC50) was deter-
mined from semilogarithmic dose-response plots, and results represent
the means ꢁSDs of three independent experiments with quadruplicate
samples each. [b] The cell lines used were: HL-60 (human promyelocytic
leukemia), HT-1080 (human fibrosarcoma), HT-29 (human colon adenocar-
cinoma), and MDA-MB231 (human breast carcinoma). [c] Value from refer-
ence [12b]. [d] Value from reference [12f].
General procedure for the ring-expansion reactions of azeti-
dine-2,3-dione 1 and indoline-2,3-diones 3
Trimethylsilyldiazomethane (0.55 mmol) was added to a solution of
the appropriate a-oxolactam 1 or 3 (0.25 mmol) and Sc(OTf)3
(11 mol%) in anhydrous dichloromethane (2 mL) cooled at 08C.
The reaction mixture was stirred at RT until the starting material
disappeared (as evident by TLC). The solvent was removed under
vacuum, and the crude product was purified by flash column chro-
matography on silica gel eluting with ethyl acetate/hexanes.[14]
pound 7d, which was the most active for all cell types assayed,
with IC50 values below one microgram per milliliter (Table 2).
Substitution of the NO2 group in this molecule by halogen
atoms, decreased the toxicity of the compound, showing the
chloro derivative to have the highest activity among the halo-
gen substituted compounds. Compounds 7 showed typical
dose-response curves for leukemia or fibrosarcoma cell lines
(Figure S1 and S2, Tables S1 and S2 in the Supporting Informa-
tion), with a sharp decrease of cell survival at concentrations
that are close to the IC50 value. Nevertheless, the dose-re-
sponse curves for these compounds show a biphasic effect on
the growth of colon or breast cancer cells (Figure S3 and S4,
Tables S3 and S4). In the first phase of the curve (at lower con-
centrations of compounds), a sharp decrease in the cell surviv-
al is observed, probably owing to an effect of the drug on pro-
liferant tumor cells. A second shift in the curve suggests a cyto-
toxic effect exerted by higher concentrations of the drug on
non-growing tumor cells. It is noteworthy that some of the as-
sayed compounds exhibited significant inhibitory effects
against the four human cancer cell lines, with IC50 values that
are similar, or even lower, to those previously reported for the
widely used etoposide or Cisplatin.[12]
Tetramic acid (+)-2a: From 52 mg (0.18 mmol) of azetidine-2,3-
dione (+)-1a, and after chromatography of the residue using ethyl
acetate/hexanes (2:1) as eluent gave compound (+)-2a (12 mg,
21%) as an orange oil; [a]D = +83.3 (c=0.6 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d=7.26 and 6.91 (d, J=9.0 Hz, each 2H),
5.28 (s, 1H), 4.72 (d, J=4.7 Hz, 1H), 4.31 (m, 1H), 3.89 (dd, J=8.9,
6.6 Hz, 1H), 3.87 and 3.81 (s, each 3H), 3.72 (dd, J=8.9, 5.5 Hz,
1H), 1.38 and 1.25 ppm (s, each 3H); 13C NMR (75 MHz, CDCl3,
258C): d=173.8, 170.5, 157.4, 129.9, 125.6, 114.3, 109.9, 95.6, 74.4,
64.4, 62.4, 58.3, 55.5, 25.8, 24.6 ppm; IR (CH2Cl2): n=1691, 1513,
1246 cmꢀ1; HRMS (ES): calcd for C17H21NO5 [M+H]+: 320.1498;
found: 320.1491.
Quinoline-2,3-dione 4b: From 50 mg (0.31 mmol) of indoline-2,3-
dione 3b, and after chromatography of the residue using n-
hexane/ethyl acetate (2:1) as eluent gave compound 4b (37 mg,
1
69%) as a white solid; m.p. 180–1828C; H NMR (300 MHz, CDCl3,
258C): d=7.52 (dd, J=7.8, 1.5 Hz, 1H), 7.46 (m, 1H), 7.36 (d, J=
8.3 Hz, 1H), 7.27 (td, J=8.4, 1.2 Hz, 1H), 7.13 (bs, 1H), 7.12 (s, 1H),
3.83 ppm (s, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=159.4, 144.2,
134.6, 127.3, 127.2, 123.2, 121.5, 114.5, 111.1, 30.3 ppm; IR (CH2Cl2):
n=3279, 1657 cmꢀ1; HRMS (ES): calcd for C10H9NO2 [M+H]+:
176.0712; found: 176.0710.
ChemPlusChem 2012, 77, 563 – 569
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General procedure for the ring expansion of imino isatins 6
Trimethylsilyldiazomethane (0.31 mmol) was added to a solution of
the appropriate imino isatin 6 (0.14 mmol) and Sc(OTf)3 (11 mol%)
in anhydrous dichloromethane (2 mL) cooled at 08C. The reaction
mixture was stirred at RT for 24 h. Then, a second batch of Sc(OTf)3
(11 mol%) and trimethylsilyldiazomethane (0.31 mmol) were
added. The solvent was removed under vacuum, and the crude
product was purified by flash column chromatography on silica gel
eluting with ethyl acetate/hexanes.
3-Aminoquinoline-2(1H)-one 7a: From 45 mg (0.13 mmol) of
imino isatin 6a, and after chromatography of the residue using n-
hexane/ethyl acetate (2:1) as eluent gave compound 7a (28 mg,
58%) as an orange oil; 1H NMR (300 MHz, CDCl3, 258C): d=7.22
(m, 10H), 7.03 (d, J=9.1 Hz, 2H), 6.85 (d, J=9.1 Hz, 2H), 5.57 (s,
2H), 3.80 and 3.36 ppm (s, each 3H); 13C NMR (75 MHz, CDCl3,
258C): d=159.7, 155.2, 143.0, 139.8, 136.5, 136.1, 128.6, 127.6,
127.2, 127.1, 126.7, 123.4, 122.3, 121.9, 121.4, 114.6, 114.4, 55.4,
46.4, 41.5 ppm; IR (CH2Cl2): n=1646, 1508, 1244, 754 cmꢀ1; HRMS
(ES): calcd for C25H25N2O2 [M+H]+: 371.1760; found: 371.1754.
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Computational methods
The DFT calculations were carried out using the B3LYP[15] ex-
change-correlation functional, together with the standard 6–31G*
basis set.[16] Optimizations were carried out using the Berny analyti-
cal gradient optimization method.[17] The stationary points were
characterized by frequency calculations, to verify that the TSs have
one and only one imaginary frequency. The IRC[18] path was traced
in order to check the energy profiles connecting each TS with the
two associated minima of the proposed mechanism by using the
second-order Gonzꢃlez–Schlegel integration method.[19] The elec-
tronic structures of stationary points were analyzed by the natural
bond orbital (NBO) method.[20] Solvent effects of CH2Cl2 (e=8.93)
were considered by single-point energy calculations using a self-
consistent reaction field (SCRF)[21] based on the polarizable contin-
uum model (PCM) of the Tomasi group.[22] Values of free energies
were calculated with the standard statistical thermodynamics at
298.15 K and 1 atm.[16] All calculations were carried out with the
Gaussian 03 suite of programs.[23]
Acknowledgements
[5] For reviews on the synthetic utility of b-lactams, see: a) B. Alcaide, P. Al-
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[6] The tetramic acid nucleus is found in many natural products, displaying
a wide spectrum of biological activities. For reviews, see: a) R. Schobert,
A. Schlenk, Bioorg. Med. Chem. 2008, 16, 4203; b) A. Gossauer, Prog.
Chem. Org. Nat. Prod. 2003, 86, 1; c) B. J. L. Royles, Chem. Rev. 1995, 95,
1981.
Support for this study by the DGI-MICINN (Projects CTQ2009–
09318 and CTQ2009–11027), Comunidad Autꢀnoma de Madrid
(Project S2009/PPQ-1752) and UCM-Santander (Grant GR35/10A)
are gratefully acknowledged. G. C. C. thanks the MEC for a pre-
doctoral grant. We thank Drug Discovery Biotech S.L. (Mꢂlaga,
Spain) for performing citotoxicity assays.
Keywords: density functional calculations
· homogeneous
catalysis · lactams · rearrangement · ring expansion · scandium
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[14] Experimental procedures as well as full spectroscopic and analytical
data for compounds not included in this Experimental Section are de-
scribed in the Supporting Information. It also contains dose-response
curves of compounds 7d and 7 f–h measured in vitro as well as cartesi-
an coordinates. It contains copies of NMR spectra for all new com-
pounds.
Received: April 16, 2012
Published online on May 23, 2012
ChemPlusChem 2012, 77, 563 – 569
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chempluschem.org
569