Synthesis of benzylidenecycloalkan-1-ones and 1,5-diketones under Claisen–Schmidt reaction: Influence of the temperature and electronic nature of arylaldehydes

Article abstract of DOI:10.1080/00397911.2017.1367819

Herein, we present the results of the influence of reaction temperature and the electronic nature of arylaldehydes in the reactions of benzocycloalkan-1-ones and arylaldehydes under classical Claisen–Schmidt condensation conditions. The products obtained, 2-arylidene derivatives of benzocycloalkan-1-ones and/or spiropolycyclic-1,5-diketones through multicomponent reactions, depended on the electronic nature of arylaldehyde and the reaction temperature. Besides, under identical conditions, 2-arylideneindan-1-ones afforded bis-indane-1,5-diketones through a process that involves Michael addition reaction, which is also dependent on the temperature. Theoretical studies using density-functional theory allowed understanding the chemical reactivity and the site selectivity of α,β-enones used in this work through the calculation of global and local electrophilicity on C–β. Both the electrophilicity of C-β and the temperature led the course of reaction toward the formation of aldol condensation, aldol condensation/Michael addition, and aldol condensation/dimerization products. This work is the first to perform the structural and configurational assignments of bis-indane-1,5-diketones.

Full text of DOI:10.1080/00397911.2017.1367819

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of benzylidenecycloalkan-1-ones and
1,5-diketones under Claisen-Schmidt reaction.
influence of the temperature and electronic
nature of arylaldehydes
Beatriz Lantaño, José M. Aguirre, Eleonora V. Drago, Mariela Bollini, Diego J.
de la Faba & Jorge D. Mufato
To cite this article: Beatriz Lantaño, José M. Aguirre, Eleonora V. Drago, Mariela Bollini, Diego
J. de la Faba & Jorge D. Mufato (2017): Synthesis of benzylidenecycloalkan-1-ones and 1,5-
diketones under Claisen-Schmidt reaction. influence of the temperature and electronic nature of
arylaldehydes, Synthetic Communications, DOI: 10.1080/00397911.2017.1367819
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1367819
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Date: 12 September 2017, At: 05:37

Synthesis of benzylidenecycloalkan-1-ones and 1,5-diketones
under Claisen-Schmidt reaction. influence of the
temperature and electronic nature of arylaldehydes
Beatriz Lantaño
Departamento de Ciencias Básicas, Universidad Nacional de Luján, Luján, Argentina
Cátedra de Química Orgánica II, Facultad de Farmacia y Bioquímica, Universidad de Buenos
Aires, Buenos Aires, Argentina
José M. Aguirre
Departamento de Ciencias Básicas, Universidad Nacional de Luján, Luján, Argentina
Cátedra de Química Orgánica II, Facultad de Farmacia y Bioquímica, Universidad de Buenos
Aires, Buenos Aires, Argentina
Eleonora V. Drago
Departamento de Ciencias Básicas, Universidad Nacional de Luján, Luján, Argentina
Mariela Bollini
Cátedra de Química Orgánica II, Facultad de Farmacia y Bioquímica, Universidad de Buenos
Aires, Buenos Aires, Argentina
Diego J. de la Faba
Departamento de Ciencias Básicas, Universidad Nacional de Luján, Luján, Argentina
1

Jorge D. Mufato
Departamento de Ciencias Básicas, Universidad Nacional de Luján, Luján, Argentina
Address correspondence to Beatriz Lantaño, Departamento de Ciencias Básicas, Universidad
Nacional de Luján, Luján 6700 Argentina; Cátedra de Química Orgánica II, Facultad de
Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (1113), Buenos Aires,
Argentina. E-mail: lantanob@gmail.com
Full experimental detail, Elemental analysis, NMR data and spectra are included.
ABSTRACT
Herein, we present the results of the influence of the reaction temperature and the electronic
nature of arylaldehydes in the reactions of benzocycloalkan-1-ones and arylaldehydes under
classical Claisen-Schmidt condensation conditions. The products obtained, 2-arylidene derivatives
of benzocycloalkan-1-ones and/or spiropolycyclic-1,5-diketones through a MCRs, depended on
the electronic nature of the arylaldehyde and the reaction temperature. Besides, under identical
conditions, 2-arylideneindan-1-ones afforded bis-indane-1,5-diketones through a process that
involves a Michael addition reaction, which is also dependent on the temperature. Theoretical
studies using density functional theory allowed understanding the chemical reactivity and the site
selectivity of the -enones used in this work through the calculation of global and local
electrophilicity on C-. Both the electrophilicity of C- and the temperature led the course of the
reaction towards the formation of aldol condensation, aldol condensation/Michael addition and
aldol condensation/dimerization products. This work is the first to perform the structural and
configurational assignment of bis-indane-1,5-diketones.
2

GRAPHICAL ABSTRACT
KEYWORDS: aldolic condensation-michael addition, benzocycloalkan-1-ones, bis-indane-1,5-
diketones, spiropolycyclic-1,5-diketones
Introduction
Natural and synthetic -unsaturated carbonyl compounds, especially chalcones, 2-
benzylideneindanones and 2-benzylidenetetralones, show significant biological activity.[1]
Besides, 2-benzylideneindanone derivatives [BI] have been shown to be potent aromatase
inhibitors in cancer therapy,[1a] potent and selective anticancer agents through the inhibition of
tubulin polymerization,[1b] and multi-target-directed ligands against neurodegenerative diseases.[1c]
In addition, Donepezil hydrochloride, an acetylcholinesterase inhibitor, has been approved by the
FDA to treat mild to moderate Alzheimer’s disease,[1d] and Indanocine and its analogs have been
developed to combat drug-resistant malignancies.[1e]
On the other hand, -unsaturated ketones are versatile and convenient intermediates in
the synthesis of a wide range of compounds. They can be used as starting materials in the synthesis
of intermediate compounds of natural products, bioactive molecules, orthogonal estrogen-
receptor-based gene switch and semiconducting thin films.[2–6] Besides, the -enone moiety of
these molecules is a favorable unit for nucleophilic 1,4-addition and dipolar cycloaddition.[2],[7],[8]
3

The most common synthetic methods to obtain -unsaturated ketones are based on
classical Claisen-Schmidt condensation conditions (C-S), which involve appropriate ketones and
aldehydes with NaOH or KOH in water-ethanol.[9] Under these conditions, high yields of several
substituted chalcones[2] and benzylidenecycloalkanones from 1-indanone and 1-tetralone and
arylaldehydes have been reported.[10] However, from arylketones with active methylenes, such as
deoxybenzoin (1) and benzaldehyde or excessive and deficient arylaldehydes, using NaOH
in EtOH/H2O, we reported a single product, the 1,5-diketone 3 known as Benzamarone (Scheme
1). In the cases studied, the benzylidene derivative 2 was not isolated and the 1,5-diketones 3 were
the result of a tandem aldol condensation–Michael addition sequence.[11]
From 1-indanones and different arylaldehydes using NaOEt in THF, Camps et al.[12]
obtained -enones and spiropolycyclic 1,5-diketones from multicomponent reactions (MCRs)
(Scheme 2). Other researchers such as Berthelette,[13a] Leblanc,[13b] Gupta[13c] and Narang[13d] used
different bases and solvents (Cs2CO3/CH3CN, KOH/MeOH at reflux temperature) and obtained
principally spiropolycyclic compounds. These results clearly indicate that the expected -enones
show a particular reactivity towards active methylene compounds and then hinder the synthesis of
BI under the classical C-S condensation thus limiting the scope of this methodology.
Based on the above, it is an interesting challenge to obtain BI with aryl groups attached to
C- with different electronic density due to their importance as precursors of several compounds,
including bis-indane 1,5-diketones. These ketones are important synthetic intermediates and
desirable starting materials for the preparation of heterocyclic and poly-functional compounds.[14]
Bearing in mind the behavior of the -enones mentioned above, in the present study, we
attempted to direct the course of the reaction towards the formation of: (i) benzylidenealkanones
(aldol condensation), (ii) bis-indane and bis-tetraline 1,5-diketones (aldol condensation/Michael
4

addition), and iii) spiropolycyclic 1,5-diketones (aldol condensation/dimerization) (Scheme 3),
and report the behavior of benzocycloalkanones, 1-indanones and 1-tetralones, and arylaldehydes
with different electronic nature using NaOH and EtOH/H2O. Changes in temperature allowed us
to direct the course of the reaction towards the desired products. In addition, in order to rationalize
the results obtained from BI, we analyzed local and global electrophilicity by using density
functional theory (DFT) methods at the B3LYP/6-31G *[15] level and compared them with other
benzylidene derivatives. This work is the first to show the structural and configurational
assignment of bis-indane 1,5-diketones by 1Dꢀ and 2Dꢀ NMR.
Results and Discussion
Reaction of benzocycloalkan-1-ones 4a, 4b, and 5 with benzaldehyde 6a under
C-S
The ketones 1-indanone (4a), 5,6-dimethoxy-1-indanone (4b) and 1-tetralone (5) were
treated with benzaldehyde (6a) at room temperature under classical C-S conditions (Scheme 4 and
Table 1). The results of these reactions allowed us to compare the behavior of these ketones with
that obtained from Deoxybenzoin (1), which led to the formation of one 1,5-diketone (3) through
aldol condensation followed by a Michael addition in tandem[11] (Scheme 1). The ketones 4a, 4b
and 5 gave the 2-Benzylidene derivatives 7a, 7b and 8inꢀ high yields [Entries 1, 13, 17]. In any
case, the corresponding 1,5-diketones were isolated, as from ketone 1.
In an attempt to assess the reactivity and to obtain the corresponding 1,5-diketones, the
-enones 7a, 7b and 8 were treated with one equivalent of the respective precursor
benzocycloalkan-1-one under C-S conditions [Table 2, Entries 1, 2, 7]. Only enones 7a and 7b
yielded the Michael addition, leading to the expected bis-indane 1,5-diketones (9a, 9a* and 9b).
5

Additionally, to favor Michael addition over compound 8, the reaction was carried out at
reflux temperature but the expected 1,5-diketone (10) was not formed [Entry 18]. However, under
these conditions, the benzylidene derivative 7a, at reflux temperature, led to a spiropolycyclic 1,5-
diketone (11a) [Entry 2]. Besides, in order to obtain the bis-tetraline 1,5-diketone 10, a change in
the stoichiometric ratio of ketone:benzaldehyde (2:1) did not lead to the expected product [Entry
19]. The same changes in the stoichiometric ratio (2:1) for ketones 4a and 4b resulted in the
formation of the expected products 9a, 9a* and 9b, at room temperature [Entries 5 and 14]. These
facts indicate the different reactivity of -enones 2, 7a, 7b and 8 with ketones with hydrogen at
C- under the conditions studied. The lack of reactivity of compound 8 can be attributed to the
lower coplanarity of the enone moiety, which decreases the electrophilicity of C-.[10]
We also studied the influence of the solvent on the course of these reactions, which were
carried out in H2O and EtOH. This assay was performed using ketone 4a. The results, shown in
Table 1, indicated that the main product in both solvents was the Benzylidene derivative (7a) and
that the EtOH/H2O mixture led to the best result since the only product formed was 7a [Entries 1,
3, 4].
Reaction of 1-indanones 4a and 4b with arylaldehydes and 2-
benzylideneindanone under C-S
The 1-indanones 4a and 4b were reacted with -excessive and -deficient arylaldehydes
under C-S conditions (Schemes 5 and 6, Table 1). The results were analyzed comparatively with
those reported by other researchers using bases and solvents different from those used in this work,
as mentioned above. The ketones 4a and 4b reacted with benzaldehyde and -excessive
arylaldehydes at room temperature with high yields to give the corresponding Benzylidene
6

derivatives (7a, 7b and 12a) [Entries 1, 13, 6]. However, at reflux temperature, the spiropolycyclic
1,5-diketones 11a and 13a, which are products of MCRs, as previously described,[12],[13] were
formed [Entries 2, 7].
The benzocycloalkan-1-ones 4a and 4b reacted at room temperature with -deficient
aldehydes, leading to the MCR products 14a, 14b and 15a [Entries 8, 16, 12]. The
benzylidenindanones 16a, 17a and 17b were obtained only when the reaction was carried out at
0°C [Entries 9, 11, 15]. In addition, using NaOH in EtOH/H2O at different reaction temperatures,
7a, 7b, 12a, 16a and 17b yielded bis-indane 1,5-diketones (Table 2). At room temperature, those
having phenyl or 4-methoxyphenyl groups yielded the expected Michael adducts (9a, 9a*, 9b and
18a). The 1,5-diketones 19a, 20a and 20b from the BIs with a -deficient aryl moiety bounded to
the C- (16a, 17a and 17b) were obtained only when the reaction was carried out at 0°C. It is
noteworthy that the reactivity of this type of -enones depends on the electronic characteristics
of the aryl moiety in C- and that by changing the temperature conditions, different products can
be synthesized (Schemes 5 and 6).
DFT study of the different reactivity of ,-enones
Conceptual DFT has been widely used to understand the chemical reactivity and the site
selectivity of molecular systems. Chemical potential (µ),[16] global hardness (),[17] global softness
[16]
(S),[16] electronegativity (, and electrophilicity ([18] are highly successful global reactivity
descriptors used to predict global chemical reactivity trends. Fukui functions[19] and local softness
are extensively applied to assess local reactivity and site selectivity. Global electrophilicity (),
introduced by Parr et al.[18] is a descriptor of reactivity which allows a quantitative classification
of the global electrophilic nature of a molecule within a relative scale, and is defined as
7

+
2Chattaraj et al.[20] proposed the generalized concept of local philicity (k ), which
provides information about nucleophilic, electrophilic and radical reactions.[21],[22] The local



electrophilicity index is defined as k = fk , where  is the global electrophilicity and fk is a
+
Fukui function.[19] The most electrophilic site in a molecule provides the highest value of k
.
We calculated global electrophilicity and local electrophilicity (C-) for Benzo -enone both in
acyclic and in cyclic compounds to analyze their reactivity (Tables 3 and 4) and to compare them
with the experimental results obtained.
The calculated global and local electrophilicity for 2, 7a and 8 showed values according to
the reactivity of ketones with active hydrogens under the classical C-S conditions (4.547 to 4.173
and 0.864 to 0.667, respectively). The higher electrophilic values of the enones studied
corresponded to ketone 2, which led to tandem reactions, showing greater reactivity than enone 7a
in identical conditions (Table 3). Finally, the benzylidene derivative 8 was not reactive under these
conditions and showed the lowest values of  and k + . This is consistent with its low reactivity,
mentioned above.
In the case of the benzylideneindanones 7a, 12a, 16a and 17a, the values of  and k are
consistent with their different reactivity since, at room temperature, the first two led to the
formation of Michael adducts, while the enones 16a and 17a, with -deficient groups bound to C-
 easily dimerized to the corresponding spiropolycyclic 1,5-diketones due to the higher values of
electrophilicity  and k + (Scheme 4 and Table 4). The benzylideneindanones 16a and 17a were
only synthesized at 0°C.
Structural and configurational assignment of the compounds synthesized
8

Benzylidene derivatives and spiropolycyclic 1,5-diketones
The benzylidene derivatives 7a, 7b, 8, 12a, 16a, 17a and 17b have been previously
described and the NMR spectroscopic data agree with previously published data.[10],[12],[23],[24] 1
H
and 13Cꢀ NMR data of the spiropolycyclic compounds 11a, 15a, 14a and 14b are consistent with
those previously reported[12],[13a] and the structure and stereochemistry of 13a was assigned by
comparison (See Supplemental data).
The structure of the spiropolycyclic compound 15a* (minor diasteroisomer of 15a) was
established by 1Dꢀ and 2Dꢀ NMR (See Supplemental data). Its relative configuration was
determined by nuclear Overhauser enhancement spectroscopy (NOESY) (Figure 2) and agrees
with one of the minor isomers described by Berthelette et al.[13a] for the reaction of 1-indanone
with benzaldehyde.
Bis-indane 1,5-diketones
These kinds of compounds can appear as four stereoisomers: two meso forms (R,s,S and
R,r,S) and one pair of enantiomers (R,R and S,S) (Figure 3). Only in the case of Michael adducts
from 7a, two diastereomers (9a and 9a*) were obtained, one of which has already been reported
by Pavel et al.[25] although its stereochemistry was not informed. All other bis-indane 1,5-diketones
were obtained as a single stereoisomer. The structural and stereochemical assignments of these
1,5-diketones were determined by NMR, chemical shifts, coupling constants and a set of 2Dꢀ
experiments: HSQC, HMBC, NOESY.
Based on HSQC experiments, hydrogens in the methylene group were assigned to both
stereoisomers of 9a and 9a* (See Supplemental data). Configurational assignment of the meso
form was determined by the NOE experiment. In this isomer, the H-3 at  2.94ppmꢀ had NOE
9

interactions with the H-10 at  3.84ppmꢀ and with the Hortho of the phenyl group, while the other
H-3 at  3.38ppmꢀ had NOE interactions only with the Hortho of the phenyl group. The H-2 at 
3.68ppmꢀ had NOE interactions with the Hortho (7.30ppmꢀ) of the phenyl group attached to C-
10. This correlation indicates that H-2 and the phenyl group of C-10 are in a cis arrangement. All
these data show that the meso-structure of the 1,5-diketone 9a has the R,s,S configuration (Figure
4, Supplemental data).
In the case of the other isomer 9a*, the H-3 at  = 2.67ppmꢀ had NOE correlation with H-
10 ( = 3.55) and with the Hortho of the phenyl group. Besides, the H-3’ at  = 3.18ppmꢀ had NOE
correlations with the Hortho of the phenyl group. The significant NOE correlation observed between
H-2 ( = 4.00ppmꢀ) and H-2’ ( = 3.82ppmꢀ) is indicative of a cis arrangement. These correlations
indicate that the structure of this isomer has the 2R,2´R/2Sꢀ,2´S configuration (Figure 5, See
Supplemental data).
Finally the structure and configuration assignment of the bis-indane 1,5-diketones
obtained, 9b, 18a, 19a, 20a and 20b, were performed by comparison of 1H NMR data with those
corresponding to 9a and 9a* (Supplemental data). All these spectroscopic data allowed us to assign
the meso configuration (R,s,S) to the bis-indane 1,5-diketones.
Conclusions
We studied the behavior of benzocycloalkan-1-ones towards arylaldehydes under classical
Claisen-Schmidt condensation conditions (NaOH in EtOH/H2O). The products obtained, 2-
benzylidene derivatives of benzocycloalkan-1-ones and/or spiropolycyclic 1,5-diketones, depend
on the electronic nature of the arylaldehyde and on the reaction temperature. Besides, 2-
arylideneindan-1-ones afforded bis-indane 1,5-diketones through a process involving Michael
10

addition reaction, which is dependent on the temperature of the reaction. Theoretical studies using
DFT allowed understanding the chemical reactivity and site selectivity of the -enones used in
this work through the calculation of global and local electrophilicity (C-. Both the
electrophilicity of C- and the reaction temperature led the course of the reaction towards the
formation of aldol condensation, aldol condensation/Michael addition and aldol
condensation/dimerization products. The results of this research indicate that bis-indane 1,5-
diketones could be synthesized with the three aryl groups with different substituents, which can be
used as starting material for the synthesis of different compounds. This work is the first to show
the dependence of the course of the reaction on both the temperature and the electrophilicity of C-
 on the reaction of benzoalkan-1-ones under C-S, NaOH in water-ethanol solution, as well as the
structural and stereochemical assignment of bis-indane 1,5-diketones.
Experimental
Reaction of benzocycloalkan-1-ones and benzaldehydes
General procedure A (Aldolic condensation)
Benzaldehyde (3.0 mmol) was added to a well stirred solution of benzocycloalkan-1-one
(3.0 mmol) and NaOH/H2O 10% (1.6mLꢀ) in ethanol (1.6mLꢀ). After the mixture was stirred at ice
bath or room temperature for 2−4hꢀ, the solid was filtered and washed with water. 2-
Arylidenebenzocycloalkan-1-ones 7a, 7b, 8, 12a, 16a, 17a and 17b were prepared as per the
mentioned procedure and identified by m.p. and 1H NMR spectra.
(E)-2-(Phenylmethylene)indan-1-one (7a)[10]
11

Yield: 0.64gꢀ (98%), mp 109-111°C (MeOH). 1H NMR (300MHzꢀ, CDCl3) 7.93 (d, J =
7.6Hzꢀ, 1H); 7.71-7.69 (m, 3H); 7.64-7.56 (m, 2H); 7.51-7.39 (m, 4H); 4.07 (s, 2H).
General procedure B (Multicomponent reactions)
Benzaldehyde (3.0 mmol) was added to a well stirred solution of benzocycloalkan-1-one
(3.0 mmol) and NaOH/H2O 10% (1.6mLꢀ) in ethanol (1.6mLꢀ). After the mixture was stirred at
reflux or room temperature for 1-2hꢀ, the reaction mixture was extracted with CHCl3 (3x10mLꢀ).
The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under reduced
pressure. The residue was purified by preparative TLC, to afford spiropolycyclic compounds. The
compounds 11a, 13a, 15a, 15a*, 14a, were prepared as per the mentioned procedure and identified
by m.p. and 1H NMR spectra.
(1RS,2SR,3SR,3aRS,8aRS)-1,3-diphenyl-3a,8a-dihydrospiro{cyclopenta[a]indene-
2,2’(1H,3’H)-indene}-1’,8(3H)-dione (11a)[13a]
Purified by preparative TLC (CHCl3). Yield: 0.79gꢀ. (60%). mp 235−236 °C (MeOH). 1H
NMR (300Hzꢀ, CDCl3) 7.77 (d, J = 7.1Hzꢀ, 1H); 7.54 (d, J = 7.6Hzꢀ, 1H); 7.48-7.40 (m, 2H);
7.31-7.09 (m, 13H); 6.94 (d, J = 7.6Hzꢀ, 1H); 4.58 (dd, J = 9.3, 9.7Hzꢀ, 1H); 4.10 (d, J = 10.8Hzꢀ,
1H); 3.93 (dd, J = 8.6, 10.6Hzꢀ, 1H); 3.84 (d, J = 10.7Hzꢀ, 1H); 3.08 (d, J = 17.4Hzꢀ, 1H); 2.99 (d,
J = 17.4Hzꢀ, 1H).
Reaction of 2-arylideneindan-1-ones and indan-1-ones
General procedure C (Michael addition)
2-Arylideneindan-1-one (3.0 mmol) was added to a well stirred solution of 1-indanones
(3.0 mmol) and NaOH/H2O 10% (1.6mLꢀ) in ethanol (1.6mLꢀ). After the mixture was stirred at ice
12

bath or room temperature for 3-5hꢀ, the solid was filtered and washed with water. The product was
purified by preparative TLC. The compounds 9a, 9a*, 9b 18a, 19a, 20a and 20b were prepared as
per the mentioned procedure. The structure of reaction products were established by spectroscopic
data.
(2R,10sꢀ,2´S)-2,2´-(phenylmethylene)-bis-(2,3-dihydro-1H-inden-1-one) (9ameso
(2R/S,2´R/S)-2,2´-(phenylmethylene)-bis-(2,3-dihydro-1H-inden-1-one) (9a*racemic
)
and
)
Purified by preparative TLC (CHCl3). Yield: 0.77gꢀ, (73%), diastereomers mixture 9a and
9a* (7:3) ratio determined by 1H NMR. 9a: mp 213-215°C[25] and 9a*: mp 173-174°C.
9a: 1H NMR (500MHzꢀ, CDCl3) δ 7.71 (d, J = 7.6Hzꢀ, 2H, H-8); 7.53 (t, J = 7.3Hzꢀ, 2H,
H-6); 7.35 (d, J = 8.2, Hz, 2H, H-5); 7.34 (t, J = 8.2, Hz, 2H, H-7); 7.30 (d, J = 7.0Hzꢀ, 2H, H-12);
7.23 (t, J = 7.0Hzꢀ, 2H, H-13); 7.14 (t, J = 7.0Hzꢀ, 1H, H-14); 3.84 (t, J = 8.0Hzꢀ, 1H, H-10); 3.68
(dt, J = 3.7, 8.0, 8.0Hzꢀ, 2H, H-2); 3.38 (dd, J = 8.0, 16.8Hzꢀ, 2H, H-3); 2.94 (dd, J = 3.7, 16.8Hzꢀ,
2H, H-3). 13Cꢀ NMR (125MHzꢀ, CDCl3): 207.5(C-1), 153.5 (C-4), 139.3 (C-11), 136.9 (C-9), 134.6
(C-6), 129.4 (C-12), 128.2 (C-14), 127.3 (C-13), 126.9 (C-7), 126.4 (C-5), 123.8 (C-8), 48.8 (C-
2), 46.4 (C-10), 31.1 (C-3). Elemental analysis calcd. (%) for C25H20O2 (352.15): C, 85.20; H,
5.72. Found: C, 85.22; H, 5.74.
9a*: 1H NMR (500MHzꢀ, CDCl3) δ 7.78 (d, J = 7.7Hzꢀ, 1H, H-8´); 7.75 (d, J = 7.7Hzꢀ, 1H,
H-8); 7.53 (t, J = 8.3Hzꢀ, 1H, H-6´); 7.51 (t, J = 7.5Hzꢀ, 1H, H-6); 7.38 (d, J = 7.5Hzꢀ, 1H, H-5´),
7.36 (overlapped, H-7); 7.34 (overlapped, H-7´); 7.33 (overlapped, H-5); 7.28 (d, J = 7.3, Hz, 2H,
H-12); 7.25 (t, J = 7.3Hzꢀ, 2H, H-13); 7.21 (t, J = 7.2Hzꢀ, 1H, H-14); 4.00 (ddd, J = 7.9, 10.6Hzꢀ,
1H, H-2), 3.82 (ddd, J = 3.6, 5.1, 8.6Hzꢀ, 1H, H-2´); 3.55 (dd, J = 3.6, 10.6Hzꢀ, 1H, H-10); 3.36
(dd, J = 8.0, 16.7Hzꢀ, 1H, H-3´b); 3.18 (dd, J = 5.3, 16.7Hzꢀ, 1H, H-3´a); 3.13 (dd, J = 7.8, 17.4Hzꢀ,
13

13
1H, H-3b); 2.67 (dd, J = 4.5, 17.4Hzꢀ, 2H, H-3a). Cꢀ NMR (125MHzꢀ, CDCl3): 207.7 (C-1),
207.1(C-1´), 153.1 (C-4), 152.8 (C-4´), 141.4 (C-11), 137.7 (C-9), 136.9 (C-9´), 134.6 (C-6), 134.2
(C-6´), 128.9 (C-7´), 128.5 (C-12), 128.3(C-13), 127.3 (C-7), 127.2 (C-14), 126.9 (C-5), 126.2 (C-
5´), 124.0 (C-8´), 123.6 (C-8), 50.2 (C-2´), 47.9 (C-10), 47.8 (C-2), 33.3 (C-3), 30.7 (C-3´).
Elemental analysis calcd. (%) for C25H20O2 (352.15): C, 85.20; H, 5.72. Found: C, 85.19; H, 5.71.
Acknowledgements
This study was supported by Universidad Nacional de Luján.
References
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15

Table 1. Reaction of 1-indanones 4a, 4b and1-tetralone 5 with arylaldehydes 6a-c.
Entry Ketone Aldehyde Ratio Method* Temp. Reaction Products (% isolated yields)
1
2
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
5
6a
6a
6a
6a
6a
6b
6b
6c
6c
6c
6d
6d
6a
6a
6c
6c
6a
6a
6a
1:1
1:1
1:1
1:1
2:1
1:1
1:1
1:1
1:1
2:1
1:1
1:1
1:1
2:1
1:1
2:1
1:1
2:1
2:1
A
A
B
C
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
25ºC
reflux
25ºC
25ºC
25ºC
25ºC
reflux
25ºC
0ºC
7a (98%)
11a (60%)
3
7a (79%) 11a(21%)
7a (56%)
4
5
7a(22%)9a(40%)/9a* (33%)
12a (87%)
6
7
13a (51%)
8
14a (98%)
9
17a(87%)14a(12%)
20a(79%)
10
11
12
13
14
15
16
17
18
19
0ºC
0ºC
16a (73%)
25ºC
25ºC
25ºC
0ºC
15a (65%)
7b(90%)
9b(75%)
17b(75%)
25ºC
25ºC
25°C
reflux
14b(20%)20b(40%)
8 (75%)
5
8
5
8
6a: Benzaldehyde; 6b: 4-MeO-benzaldehyde; 6c: 4-PyCHO; 6d: 3-PyCHO.
*A: NaOH/EtOH/H2O; B: KOH/EtOH; C: NaOH/H2O.
16

Table 2. Reaction of 2-benzylidencycloalkan-1-ones with ketones 4a, 4b and 5.
Entry
2-enones
7a
ketones
4a
Temp.
25ºC
25ºC
25ºC
0ºC
Products
1
2
3
4
5
6
7
9a/9a* (7:3)
7b
4b
9b
12a
16a
17b
17b
8
4a
18a
4a
19a
4b
25ºC
0ºC
14b/20b(2:1)
4b
20b
8
5
25ºC
17

k
Table 3. Global () and local (
of C-) electrophilicity values of ,-enones2, 7aand 8.
fk
k
Compound



2
-3.821
-4.166
-4.045
1.605
2.026
1.961
4.547
4.282
4.173
0.191
0.170
0.165
0.864
0.728
0.667
7a
8
Values are in eV.
18

k
Table 4. Global () and local (
12a, 16aand 17a.
of C-) electrophilicity values of Benzylideneindanones 7a,
fk
k
Compound
Ar



12a
7a
4-CH3OPh
Phenyl
-3.808
-4.166
-4.366
-4.466
1.920
2.026
2.026
2.078
3.775
4.282
4.704
4.799
0.157
0.170
0.172
0.171
0.566
0.728
0.799
0.811
16a
3-Pyridyl
4-Pyridyl
17a
Values are in eV.
19

Figure 1. Benzilidene derivatives.
20

Figure 2. Representative NOE correlations of spiropolycyclic 15a*.
21

Figure 3. Stereoisomers of the bis-indane1,5-diketone 9.
22

Figure 4. Representative NOE correlations of 9a (meso form R,s,S).
23

Figure 5. Representative NOE correlations of racemic 9a*(2R,2’R/2Sꢀ,2’S).
24

Scheme 1. Aldol condensation and Michael addition products from deoxybenzoin.
25

Scheme 2. Aldol condensation and MCR products from 1-indanone.
26

Scheme 3. Reactions of benzocycloalkanones and benzylidenealkanones.
27

Scheme 4. Reaction of benzocycloalkan-1-ones (4a, 4b, and 5) with benzaldehyde.
28

Scheme 5. Reactions of 4a with arylaldehydes and 2-arylideneindanones.
29