Site-selectivity control in hetero-Diels-Alder reactions of methylidene derivatives of lawsone through modification of the reactive carbonyl group: An experimental and theoretical study

Article abstract of DOI:10.1039/c8ob02383b

A new perspective on the reactivity of hydroxyquinones was revealed as an acetal derivative of lawsone was synthesized, isolated, and used in tandem Knoevenagel/hetero-Diels-Alder reactions catalyzed by S-proline. The intermediate alkylidene-1,3-diones that were formed in situ reacted with electron rich alkenes to predominantly afford pyrano-1,2-naphthoquinone (β-lapachone) derivatives along with the isomeric pyrano-1,4-naphthoquinone (α-lapachone) derivatives in high to excellent total yields. Interestingly, the highly reactive arylidene-1,3-dione derivatives were found to be stable and isolable. DFT calculations suggest that these hetero-Diels-Alder reactions have a high polar character, taking place through a two-stage one-step mechanism. An analysis of the conceptual DFT indices allows explaining the remarkable site-selectivity observed.

Full text of DOI:10.1039/c8ob02383b

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Site-selectivity control in hetero-Diels–Alder
reactions of methylidene derivatives of lawsone
through modification of the reactive carbonyl
group: an experimental and theoretical study†
Cite this: Org. Biomol. Chem., 2019,
17, 692
Maria Tsanakopoulou, a Erifili Tsovaltzi,a Marina A. Tzani, a Periklis Selevos,a
Elizabeth Malamidou-Xenikaki, *a Evangelos G. Bakalbassisb and
c
Luis R. Domingo
A new perspective on the reactivity of hydroxyquinones was revealed as an acetal derivative of lawsone
was synthesized, isolated, and used in tandem Knoevenagel/hetero-Diels–Alder reactions catalyzed by
S-proline. The intermediate alkylidene-1,3-diones that were formed in situ reacted with electron rich
alkenes to predominantly afford pyrano-1,2-naphthoquinone (β-lapachone) derivatives along with the iso-
meric pyrano-1,4-naphthoquinone (α-lapachone) derivatives in high to excellent total yields. Interestingly,
the highly reactive arylidene-1,3-dione derivatives were found to be stable and isolable. DFT calculations
suggest that these hetero-Diels–Alder reactions have a high polar character, taking place through a two-
stage one-step mechanism. An analysis of the conceptual DFT indices allows explaining the remarkable
site-selectivity observed.
Received 25th September 2018,
Accepted 18th December 2018
DOI: 10.1039/c8ob02383b
rsc.li/obc
ditions (Scheme 1)4 and to α,β-unsaturated carbonyl com-
pounds as will be discussed below. Interestingly, functionali-
Introduction
The synthesis of hydroxyquinone derivatives is of great impor- zation of the 3-position with
a phenyliodonium group
tance in organic chemistry as these compounds consist of ver- enriched the chemistry of lawsone by providing the opportu-
satile synthetic intermediates.1 A characteristic example of this nity for the formation of new 3-aryl and 3-styryl substituted
class of compounds is lawsone (2-hydroxy-1,4-naphthoqui- 2-hydroxynaphthoquinone derivatives.5–9
none, 1) which was isolated from the henna plant (Lawsonia
Continuing our studies on the reactivity of hydroxyquinones
inermis) and has been extensively studied.2 Lawsone (1) can be and their potential cyclized derivatives, pyranonaphthoqui-
considered as the stable enol form of a β-diketone that can be nones attracted our interest, especially as these compounds
either O-alkylated or C-alkylated. Lapachol [2-hydroxy-3-(3- exhibit a range of important biological activities. More specifi-
methylbut-2-en-1-yl)naphthalene-1,4-dione, 2] was obtained in cally, β-lapachone (3) is a naturally occurring pyrano-1,2-
low yield from the reaction of a lithium salt of lawsone with di- naphthoquinone, which was isolated from the lapacho tree
methylallyl bromide,3a whereas the palladium-catalysed allyla- (Tabebuia avellanedae)10 and showed significant antineoplastic
tion of lawsone with allyl alcohols and allyl esters3b offered activity against various human cancer cells without affecting
an easy access to 3-allyl-2-hydroxy-1,4-naphthoquinones. the non-cancerous cells.2,11,12 After searching the literature, we
Alternatively, C-alkylation was achieved via the Michael realized that hydroxynaphthoquinones, which represent excel-
addition of lawsone (1) to nitroolefins under aqueous con- lent starting materials for the synthesis of pyranonaphthoqui-
nones, predominantly yielded the pyrano-1,4-naphthoquinone
(α-lapachone, 4) derivatives. β-Lapachone (3) exhibits more
remarkable biological activities than its α-isomer 4 and, thus,
aLaboratory of Organic Chemistry, School of Chemistry, Faculty of Sciences,
Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
we decided to investigate the potential reactivity of lawsone (1)
toward the synthesis of β-lapachone derivatives.
Regarding the known syntheses of pyranonaphthoqui-
nones, we will discuss herein the ones related to the present
work. Sulfuric acid catalyzed cyclization of lapachol (2)
afforded the angular β-lapachone (3) as the C-2 hydroxyl group
attacked the protonated double bond, while the hydrochloric
E-mail: malamido@chem.auth.gr; Fax: (+30) 2310 997679; Tel: (+30) 2310 997874
bLaboratory of Applied Quantum Chemistry, School of Chemistry, Faculty of Sciences,
Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
cUniversidad de Valencia, Departamento de Química Orgánica, Dr Moliner 50,
E-46100 Burjassot, Valencia, Spain
†Electronic supplementary information (ESI) available: Detailed experimental
procedures, copies of NMR spectra and computational data. See DOI: 10.1039/
c8ob02383b
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water, this changed dramatically to 0.6–0.8 for the reactions
with arylaldehydes. Accordingly, the Knoevenagel conden-
sation of lawsone (1) with an aldehyde bearing a remote
double bond, like citronellal, led to the tandem intramolecular
hetero-Diels–Alder reaction of the alkylidene-1,3-dione
intermediate and the synthesis of tetracyclic α- and
β-pyranonaphthoquinones (Scheme 1e).16b,23 However, the
selectivity of these reactions was low and the ratio of α : β lapa-
chone polycyclic derivatives ranged from 1.0 to 0.6.
Our interest was drawn to the one-pot synthesis of lapa-
chone derivatives through domino Knoevenagel/hetero-Diels–
Alder (DKHDA) reactions. Considering the electrophilic charac-
ter of the heterodiene participating in this hetero-Diels–Alder
reaction, we reasoned that the site-selectivity would be driven
by the C-1 carbonyl of lawsone (1). Therefore, this carbonyl has
the potential to attract electrons and, thus, further increase
the reactivity of the electron poor α-heterodiene compared to
the remote β-heterodiene (depicted as and , respectively, in
Scheme 1) that is also present in the molecule. We thus envi-
saged that the site-selectivity of the cycloaddition could be
altered in favor of the desired β-lapachone derivatives by
amending the effect of the carbonyl at C-1, which is also the
most reactive one of lawsone (1). For this purpose, we decided
to investigate the effect of the modification of this carbonyl to
an acetal group, which would be bulkier and less electron
Scheme 1 Synthetic approaches to pyranonaphthoquinones starting
from hydroxynaphthoquinones.
acid catalyzed reaction led to the synthesis of the linear withdrawing. Subsequently, we studied the site-selectivity of
α-lapachone (4) by an alternative attack of the C-4 quinonic the cycloaddition reactions with electron rich dienophiles
oxygen (Scheme 1a).13 However, this synthetic method is aiming at the selective formation of β-lapachone derivatives
limited by the low yielding synthesis of lapachol (2).3 and herein we report our experimental results along with our
Furthermore, the Michael addition of lawsone (1) to DFT theoretical studies, which are in total agreement.
α,β-unsaturated carbonyl compounds followed by sodium
borohydride reduction and acid-catalyzed cyclization led exclu-
sively to α-lapachone derivatives (Scheme 1b).14,15 Similar pro-
ducts were obtained from the base-catalyzed addition of
Results and discussion
Chemistry
lawsone to α,β-unsaturated aldehydes followed by electrocycli-
zation (Scheme 1c).16 These dehydro-α-lapachones could then
Our plan of differentiating the reactivities of the two hetero-
be converted to α-lapachones by palladium-catalyzed hydroge-
nation.16d,17 Regarding other examples of addition/cyclization
cascade organocatalyzed reactions of hydroxynaphthoquinones
with α,β-unsaturated carbonyl compounds, only the
α-lapachone derivatives were initially obtained.18 These pro-
ducts were then efficiently isomerized to the β-isomers in an
extra synthetic step, which inevitably decreased the total yield
of the synthesis.18b Interestingly, another pyranonaphthoqui-
none synthesis derived from the Knoevenagel condensation of
lawsone (1) with aldehydes in refluxing dioxane that was fol-
lowed by the Diels–Alder reaction with alkenes, enol ethers19
or silyl enol ethers (Scheme 1d).20 The reaction mixtures con-
tained either exclusively α-lapachones20 or both α- and
β-lapachone derivatives19 that were usually enriched in the α
isomer (α : β ratio: 0.94–3.75). This attractive three-component
one-pot protocol was mostly limited to Knoevenagel conden-
sations with formaldehyde.21 In the case of arylaldehydes in
ethanol/water solvent, the rate, regioselectivity and yield of the
reaction were improved.22 Although the α : β ratio was found to
diene moieties of the 3-methylidene derivatives of lawsone was
based on information from the literature for several hetero-
Diels–Alder reactions which are considered polar, asynchro-
nous one-step processes.24,25 Their feasibility has been related
to the electrophilic and nucleophilic character of each one of
the two reagents, and hence to the polar character of the tran-
sition state structure (TS).26
We carried out a preliminary theoretical study for the
model compounds 6, 7, 8, and 9 (Fig. 1) bearing only one het-
erodiene group. This study verified the significant effect of the
carbonyl group acetalization on the ω value of model com-
pound 7 compared to that of 6 (see later, Table 2). We found
that acetalization of the carbonyl group reduces the electrophi-
be 3.1–4.7 for the reactions with formaldehyde in ethanol/ Fig. 1 Model compounds used for the theoretical study.
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licity of the α-heterodiene functional group. On the other 2.2 : 1 or 3.4 : 1 depending probably on the concentration of
hand, a similar transformation of the model compound 8 the contextual CDCl3 solution and perhaps on the quality of
toward acetal 9 resulted in a smaller decrease of the calculated the solvent. Although acetal 12 is readily hydrolyzed upon
ω value, signaling a favorable effect on the reactivity of the standing, it can be kept unchanged for a long time in a
β-heterodiene functional group. An even greater effect resulted freezer.
from the analogous acetalization of compound 5 affording 10.
We first tried the reaction of 12 with aldehyde 13b applying
Obviously, acetalization of the CvO group affects the electro- conditions (Table 1, entry 1) similar to the ones described in
philicity of the α-heterodiene group to a greater extent than the literature23 for in situ reactions of lawsone with aldehydes.
that of the β-heterodiene.
The alkylidene derivative 14b was isolated in low yield (10%).
Based on the encouraging theoretical results above, we pre- In order to optimize the reaction conditions, a series of experi-
pared the acetal of lawsone 12, in very good total yield, ments presented in Table 1 were conducted. Reactions were
through a two-step course (Scheme 2). The acetate 11 27 was performed in various solvents (CH2Cl2, C6H6, DME, and
initially prepared upon treatment of lawsone with acetic anhy- MeOH) and basic catalysts (K2CO3, pyrrolidine, DMAP, glycine,
dride and isolated by filtration in 93% yield. The most electro- L-alanine, DL-piperidin-2-carboxylic acid, and S-proline), under
philic carbonyl group of 11 was then selectively acetalized in a reflux, microwave irradiation (MW) or at rt, but without signifi-
methanolic suspension of K2CO3. Efforts to form such acetal cant improvement of the yield. Addition of anhydrous MgSO4
derivatives by directly applying the conventional acid catalyzed proved to be essential as it resulted in a spectacular increase
process were unsuccessful due to the activation of all three car- in the yield of product 14b (entries 7 and 11). The effect of the
bonyl groups in nucleophilic attacks through tautomerization. ratio of the reactants was also investigated by using an excess
Acetal 12 was isolated by crystallization in 84% yield and it was of the aldehyde from 1 : 1 to 1 : 3 (Table 1, entries 11, 12, and
found to exist in equilibrium with its keto form in CDCl3 solu- 13). Interestingly, a twofold excess of the aldehyde gave 73%
tion according to the NMR data that we recorded. In different yield of the product 14b (entry 12). The optimal reaction con-
1H NMR experiments, the keto/enol ratios varied from 1.9 : 1 to ditions were used for the preparation of all the arylidene-1,3-
diones 14 and are outlined as follows: stirring of a solution of
12 and 13 (ratio 1 : 2) in CH2Cl2 at rt, in the presence of anhy-
drous MgSO4 and an S-proline catalyst (20 mol%).
The arylidene compounds 14 were obtained in very good
yields (Scheme 3) and isolated in pure state from the reaction
mixture by column chromatography in the form of the
Z-isomer, although indications exist for the formation of small
amounts of the E-isomer. The isolation of one stereoisomer 14
in very good yield is rather indicative of the remarkable stereo-
selectivity of the above reaction. Arylidene-1,3-diones 14 are
stable compounds and can be stored for a long time in the
freezer.
We base the elucidation of the stereochemical structure of
3
the new isolable compounds 14 on their JCH coupling con-
stants between the C-1 and C-3 carbonyl carbons with the
alkenyl hydrogen. As depicted in Fig. 2, the C-3 (δ = 194.2) and
Scheme 2 Preparation of the starting acetal 12.
Table 1 Optimization of conditions for the preparation of arylidene-1,3-dione 14b
Solvent
12 : 13b
Catalyst (dehydrating agent)
Temperature (°C)
Yield (%)
1
2
3
4
5
6
7
8
MeOH
DME
C6H6
1 : 1
1 : 1
1 : 1
1 : 2
1 : 2
1 : 2
1 : 1
1 : 2
1 : 2
1 : 2
1 : 1
1 : 2
1 : 3
Ethylenediamine·2HCl
Ethylenediamine·2HCl
S-Proline
Reflux
80
80
45
80 (MW)
25
25
25
25
25
10
—
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
S-Proline
21
—
0–20
10
30
—
—
52
73
76
S-Proline
a
S-Proline
S-Proline
S-Proline
S-Proline (DCC)
S-Proline (MgSO4)
S-Proline (MgSO4)
S-Proline (MgSO4)
9
10
11
12
13
25
25
25
a Various catalysts were tested: glycine, L-alanine, pyrrolidine, DMAP, K2CO3, DL-piperidine-2-carboxylic acid.
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the presence of a dienophile. After 30 min at 0 °C, an excess of
ethoxyethene (17a) was added and the mixture was stirred at
room temperature overnight. Products 18a and 19a were
formed and then isolated by column chromatography in 16%
and 75% yields, respectively (Scheme 5). Under these opti-
mized conditions, the analogous reactions with some β- (17b)
or α-substituted (17c) and cyclic enol ethers (17d,e) were per-
formed and the products 18b,d,e and 19b,d,e were isolated in
good to excellent yields. In the case of dihydropyran 17e the
total yield appears relatively reduced, possibly due to steric
effects. The very low yield in the case of 17c is due to the for-
mation of by-products, as will be discussed below.
Scheme 3 Preparation of the stable 2-arylidene-1,3-diones 14.
The distinction between isomers 18 and 19 was based on
1
their H NMR and 13C NMR spectra. Specifically, the 13C NMR
peak for the more conjugated carbonyl carbon of the dihydro-
benzo[g]chromenones 18 appeared upfield (δC between 183.8
and 183.4 ppm) relative to that of the dihydrobenzo[h]chrome-
nones 19 (δC between 192.9 and 192.3 ppm). On the other
hand, the aromatic hydrogens of the compounds exhibit
3
Fig. 2 JCH coupling constants of compound 14c.
1
characteristic patterns in the H NMR spectrum. In the spec-
C-1 (δ = 185.4) carbonyls of 14c appear as a doublet (3JCH
=
trum of 19 all aromatic hydrogens resonate between 7.42 and
7.87 ppm. The two doublets for the hydrogens adjacent to the
junction give distinguishable peaks at 7.87–7.79 and
7.70–7.69 ppm, whereas the peaks of the other two hydrogens
are very close and almost overlap each other at 7.49–7.47 and
7.46–7.42 ppm. In contrast, the 1H NMR spectra of the isomers
18 show separate peaks for each of the four aromatic hydro-
gens, three of them at 7.72–7.68, 7.64–7.60 and 7.51–7.50 and
one, corresponding to the hydrogen positioned ortho to the
carbonyl group, at lower field values of 8.12–8.09 ppm.
The results of the above reactions fully verify the theoretical
predictions. Indeed, the transformation of the carbonyl func-
tional group into its corresponding acetal appears to contrib-
ute to the reversal of the site-selectivity of the DKHDA reac-
tions of lawsone. The reactions of the unsubstituted and
β-substituted open chain enol ethers 17a,b with the in situ gen-
erated alkylidene-1,3-dione 10 exhibit excellent selectivity
10.6 Hz) and a doublet of doublets (3JCH = 7.2, 4.2 Hz), respect-
ively. In accordance with the literature,28,29 the greater J value
3
is assigned to the carbonyl carbon positioned trans to the
alkenyl hydrogen, namely C-3.
The selective formation of the Z-isomer, which, inciden-
tally, was calculated to be more stable by 0.4 kcal mol−1 than
the E-isomer for 14b (Table S3†), could be attributed to the
catalytic activity of proline whose action as an effective organo-
catalyst in asymmetric aldol reactions30 is well known. With
regard to the mechanism, we assume that the reaction of
S-proline with arylaldehyde 13 results in the asymmetric
iminium ion 15 (Scheme 4) which is subsequently attacked by
β-diketone 12. A hydrogen bonded intermediate like 16 pro-
vides stereochemical selectivity. Analogous iminium ions have
been reported to mediate in asymmetric Michael additions18b
of lawsone to α-unsaturated aldehydes.
Considering the above good results we tried the reaction of
acetal 12 with HCHO in order to prepare the methylidene
derivative of lawsone 10. In particular, the acetal 12 reacted
with an aqueous solution (37%) of formaldehyde (3.6 equiv.)
in CH3CN, at 0 °C, in the presence of a catalytical amount of
S-proline and anhydrous MgSO4 as the dehydrating agent.
After 1 day at rt, the isolation of product 10 was not possible
due to its high reactivity. In order to trap the alkylidene deriva-
tive 10 as a Diels–Alder product, the reaction was repeated in
Scheme 4 Proposed mechanism for the proline-catalyzed stereo-
selective synthesis of arylidene-1,3-diones 14.
Scheme 5 Reactions of the in situ generated alkylidene-1,3-diones 10
with alkyl vinyl ethers 17.
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toward the cycloaddition product of the β-heterodiene group tion of lawsone with 2-methoxy-1-propene is referred19 to give
19a,b, the product α : β ratio ranging from 0.21 to 0.25. The only the α-lapachone derivative in 60% yield.
site-selectivity decreases significantly in the case of cyclic
Both results recorded in Scheme 5 for the hetero-Diels–
ethers 17d,e (α : β = 1.21). The calculated nucleophilicity Alder reaction of compound 10 with ethoxyethene (17a) and
indexes suggest that they, along with steric factors, play an that reported in the literature for the corresponding reaction
important role. In analogous DKHDA reactions of lawsone of 5 are in excellent agreement with the theoretical study that
with HCHO and 2-(methoxyvinyl)benzene or ethoxyethene we carried out (see the theoretical study below).
mentioned in the literature,19 the α : β ratio is 3.75 and 1.67,
In our effort to synthesize heterodiene analogues of 14
respectively. Furthermore, the isolation of product α, in 60% from aliphatic aldehydes, we attempted the reaction of 12 with
yield, is only referred from the corresponding reaction with acetaldehyde under conditions similar to those applied earlier
1-(vinyloxy)butane. With respect to the reaction of 17e, pro- for formaldehyde. When the reaction with an excess of acet-
ducts of the α (18e) and β (19e) series were formed in yields of aldehyde was performed at rt in CH2Cl2 using S-proline as the
34% and 28%, respectively, while for the corresponding reac- catalyst and anhydrous MgSO4 as the dehydrating agent, the
tion of lawsone, the formation of the analogous β product, in products 25 and 26 were isolated as a non-separable mixture
yield 12%, was only reported.31
in 95% total yield and in a ∼1 : 8.5 ratio as estimated by 1H
In the case of 2-methoxypropene (17c), product 19c predo- NMR (Scheme 7). In our attempt to separate the products 25
minates again, but the selectivity of the reaction is noticeably and 26 by silica column chromatography we observed their
reduced (α : β ratio: 0.66). Both the reduced yield and the lower hydrolysis. The products apparently derived from the in situ
selectivity of this reaction could be attributed to stereochemi- generated Knoevenagel condensation product 24, which then
cal factors. Regarding the low yields of the products, it should participated in a hetero-Diels–Alder reaction with the acet-
be noted that, in addition to products 18c and 19c, the unex- aldehyde enolate. The relative ratio 25 : 26 confirms, once
pected products 22 and 23 were also isolated in yields of 11% again, the excellent site-selectivity of the cycloaddition. High
and 27%, respectively (Scheme 6). These products could be selectivity was also shown by the same reaction when carried
derived from an analogous DKHDA process in which the out in the presence of ethoxyethene 17a from which the pro-
Knoevenagel condensation product 21 is initially formed from ducts 27 (yield 9%) and 28 (78%) were obtained.
the reaction of acetal 12 with acetone, deriving probably from
Equally remarkable site-selectivity, and at the same time
the partial hydrolysis of enol ether 17c, and is then subjected excellent stereoselectivity, was also demonstrated by the
to a hetero-Diels–Alder reaction with 17c. Nevertheless, when hetero-Diels–Alder reactions of the stable heterodienes 14b,c
acetone was used instead of HCHO in the reaction of 12 with with ethoxyethene (17a), with which our research effort contin-
17c, under similar conditions, the products 22 and 23 were not ued. These reactions took place under mild conditions
detected. In Scheme 6, a possible route for the formation of (CH2Cl2, rt) and afforded the four cycloaddition products
these products is proposed, which involves protonation of the 29–32a,b depicted in Scheme 8, in quantitative total yields.
methoxy group of 17c, perhaps by the S-proline or the acidic Both products 29, 30 and 31, 32 are pairs of diastereomers
acetal 12, and its subsequent nucleophilic attack by 12.
Elimination of methanol from the intermediate 20 results in
the unstable heterodiene 21 from which the cycloaddition pro-
ducts 22 and 23 are finally formed upon the reaction with 17c.
Following this observation, the overall yield of the cyclo-
addition products coming from the α-heterodiene group rises
up to 23% and that derived from the β-heterodiene group to
45% (overall α : β ratio: 0.51). In contrast, the analogous reac-
Scheme 6 A plausible mechanistic scheme for the formation of pro-
ducts 22 and 23.
Scheme 7 Reactions of the in situ generated ethylidene derivative of
lawsone 24 with acetaldehyde and ethoxyethene.
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When the reactions were carried out at rt, that is under con-
ditions analogous to those applied for the reactions of the
enol ethers 17, the observed overall yields of products 34 and
35 were low in the case of dienophiles 33a (22%) and 33c
(13%) and moderate for 33b (48%). This is to some extent due
to steric factors, particularly in the case of 33c, and simul-
taneously seems consistent with the relatively higher values of
the calculated electrophilicity indexes, ω,32 in combination
with the lower values of the nucleophilicity indexes, N,33 as
compared to that of the enol ethers 17 (see below Table 2).
Because of the difficulty of quantitatively separating products
34 and 35, their relative proportions were evaluated from the
1H NMR spectra of their crude mixtures as isolated by column
chromatography. The estimated α : β (34 : 35) ratios were
1 : 1.48, 1 : 1.1 and 1 : 0.95 in the cases of dienophiles 33a, 33b
and 33c, respectively, reflecting the dependence of the site-
selectivity on steric hindrances of dienophiles.
In an attempt to increase the yield and possibly improve
the relative proportion of the products, the DKHDA reaction of
10 with HCHO and styrene 33a was carried out under analo-
gous conditions but in different solvents (CH2Cl2 and dioxane)
or by using different energy sources. More specifically, thermal
(reflux in ethanol solution), ultrasound (sonication in dioxane
solution) or microwave irradiation (irradiation of the reactants
in a microwave oven, in CH2Cl2, at 65 °C, 70 °C or 75 °C) was
applied. The best result was obtained in the latter case where
both consumption of all starting acetal 12 and the highest
overall yields were observed.
These optimal conditions were also applied to the reactions
of 10 with the alkenes 33b and 33c. The yield of the reactions
increased, but in addition to the desired products 34 and 35,
their hydrolysis products 36 and 37 were also detected
(Scheme 9). More specifically, under the intense reaction con-
ditions that were applied, the products 36 and 37 could have
derived either from the hydrolysis of the products 34 and 35 or
from the hydrolysis of the intermediate 10 to 5 and a cyclo-
addition reaction with alkenes 33 or hydrolysis of the acetal 12
to lawsone 1 and a reaction with formaldehyde and then with
alkenes 33. Due to the almost identical Rf of the products 34,
35 and 36, the separation of the mixture by silica column
chromatography was inefficient. Even though we did not purify
the products in this instance, we could easily estimate the
ratio of the products 34 and 35 by relative integration of the
peaks of the methoxy groups in the 1H NMR spectra of the
crude mixtures. The α : β ratios found for the products
34a : 35a, 34b : 35b, and 34c : 35c were 1 : 1.75, 1 : 1.29, and
1 : 1.19, respectively, indicating again the site-selectivity for the
β-cycloadducts, albeit significantly reduced. As reported in the
literature,21 the same reactions of lawsone (1) carried out via
the intermediate 5 by heating in ethanol/water 1 : 1 gave
almost quantitative overall yields, but the α : β ratio of the pro-
ducts ranged between 1 : 0.33 and 1 : 0.25. We then repeated
the MW reaction and the crude mixture was hydrolyzed with
TFA. The final mixtures of the hydrolyzed products 36 and 37
were purified by column chromatography in order to verify the
formation of the cycloaddition products and to determine the
Scheme 8 Hetero-Diels–Alder reactions of the stable arylidene deriva-
tives of lawsone 14 with ethoxyethene.
derived from the endo (29, 31) or exo (30, 32) cycloaddition
mode of the dienophile to the β- and α-heterodiene group,
respectively. The separation of the products was laborious and
was accomplished by successive chromatography columns.
The stereochemical structure elucidation of the products was
based on NOESY experiments from which a syn-configuration
for the 2-H and 4-H of the pyran ring was assumed in the case
of cycloadduct 29a and an anti-configuration for the same
hydrogens in the case of 31a.
Our findings suggest that both the yields and the site-
selectivity of the hetero-Diels–Alder reactions studied are very
good with the activated dienophiles. Furthermore, they are vir-
tually unaffected by the alkylidene group substitution of the
substrates, but both are significantly affected by the degree of
substitution and the stereochemical hindrance of dienophiles.
We also investigated the analogous hetero-Diels–Alder reac-
tions of the in situ formed alkylidene compound 10 with the
less activated alkene dienophiles 33a–c (Scheme 9). Due to the
absence of a 2-alkoxy substituent on the pyran ring, the
expected cycloadducts are supposed to be more stable than
their analogs coming from the DKHDA reactions of 12 with
aldehydes and enol ethers. The possibility of the pyran ring
opening, which is observed in the latter products upon long
standing at rt, and which is due to their acetal nature, is cer-
tainly eliminated.
Scheme 9 Reactions of the in situ generated arylidene-1,3-dione 10
with alkenes 33 under MW irradiation.
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reaction yields (58% for 10/33a, 71% for 10/33b, and 28% for phile participating in polar Diels–Alder reactions. Similarly,
10/33c) that greatly increased compared to those of the reac- dicarbonyl compounds 6 and 8 present high electrophilicity
tions at rt. It is remarkable that even the less activated alkene indices, ω = 2.80 eV and 2.35 eV, respectively. Finally, acetaliza-
dienophiles 33a–c showed again site-selectivity in the DKHDA tion of one of the two carbonyl groups of compounds 6 and 8
reaction with acetal 12, validating once again that the latter markedly decreases their electrophilicity ω index to 1.80 eV (7)
constitutes an excellent tool for the synthesis of β-lapachone and 1.91 eV (9). Note that although the acetalization of
derivatives.
one carbonyl group notably reduces the electrophilicity of
the precursor compound, the acetal 10 possessing two
carbonyl groups participates in polar hetero-Diels–Alder
reactions.
On the other hand, ethylene derivatives 17a–d and 33a–c
have nucleophilicity N indices ranging from 2.98 (33c) eV to
3.56 (17d) eV. Thus, while ethylene 33c is located on the bor-
derline of a moderate nucleophile, the other ethylene deriva-
tives are classified as strong nucleophiles.34
Consequently, it is expected that the hetero-Diels–Alder
reactions of heterodienes 5, 10, 6 and 8 with the electron-rich
ethylenes 17a–d and 33a–c will have a highly polar character,
and very low activation energy (see later).
Theoretical study
Analysis of the conceptual DFT indices at the ground state of the
reagents
Numerous studies devoted to polar and ionic organic reactions
have shown that the analysis of the reactivity indices defined
within Conceptual DFT (CDFT)34 is a powerful tool to predict
and understand the reactivity in polar reactions. The global
indices, namely, the electronic chemical potential, μ, chemical
hardness, η, electrophilicity, ω, and nucleophilicity, N, of the
reagents involved in these hetero-Diels–Alder reactions are
given in Table 2.
Polar Diels–Alder reactions involving non-symmetrical sub-
stituted reagents present complete regioselectivity. The more
favorable regioisomeric reaction path is that associated with a
two-center interaction between the most electrophilic center of
the electrophile and the most nucleophilic center of the
nucleophile. Analysis of the Parr functions37 permits character-
izing these relevant centers, allowing us to explain the com-
plete regioselectivity experimentally observed. The most elec-
The electronic chemical potentials35 µ of the ethylene
derivatives 17a–d and 33a–c, between −3.43 (33a) and −2.18
(17b) eV, are higher than those of heterodienes, between −5.04
(5) and −4.06 (7) eV (see Table 2). These values suggest that
along these polar hetero-Diels–Alder reactions, the Global
Electron Density Transfer36 (GEDT) will flux from the ethylenes
towards the heterodienes.
The feasibility of a polar Diels–Alder reaction has been
related to the polar character of the reaction measured through
the analysis of the GEDT at the corresponding TSs.26,36 This be-
havior can be anticipated analyzing the global electrophilicity32
ω and nucleophilicity33 N indices at the GS of the reagents.
Compound 5 possessing three carbonyl groups is the most
electrophilic species of this series of heterodienes, ω = 3.31 eV,
being classified as a strong electrophile.34 Acetalization of one
carbonyl group in compound 10 (Fig. 1) decreases its electro-
philicity to 2.44 eV, being also classified as a strong electro-
+
trophilic Pk Parr function of 10, and the most nucleophilic
−
Pk Parr function of vinyl ether 17a are given in Fig. 3. While
+
at heterodiene 10 the terminal ethylene C1 carbon, Pk = 0.57,
presents the highest electrophilic Parr value, the non-substi-
−
tuted C5 carbon of vinyl ether 17a, Pk = 0.62, presents the
highest nucleophilic Parr value.
Consequently, it is expected that the more favorable regio-
isomeric reaction path will be that associated with the nucleo-
philic attack of the C5 carbon of vinyl ether 17a on the C1
carbon of heterodiene 10, in complete agreement with the
experimental outcomes.
+
Interestingly, the electrophilic Pk Parr functions at the β
carbonyl group, 0.14 at the carbon and 0.13 at the oxygen, are
Table 2 The electronic chemical potential, µ, chemical hardness, η,
electrophilicity, ω, and nucleophilicity, N, indices of the reagents involved
in the hetero-Diels–Alder reactions
µ
η
ω
N
5
6
14b
10
8
9
7
33a
33b
33c
17a
17c
17e
17d
17b
−5.04
−4.64
−4.44
−4.53
−4.62
−4.28
−4.06
−3.43
−3.31
−2.55
−2.41
−2.32
−2.25
−2.20
−2.18
3.83
3.84
3.83
4.21
4.54
4.80
4.56
5.20
5.42
7.17
7.22
7.26
6.93
6.71
7.02
3.31
2.80
2.57
2.44
2.35
1.91
1.80
1.13
1.01
0.45
0.40
0.37
0.37
0.36
0.34
2.16
2.56
2.77
2.48
2.23
2.44
2.78
3.09
3.10
2.98
3.10
3.17
3.40
3.56
3.43
Fig. 3 3D representations of the Mulliken atomic spin density of the
radical anion 10•− and the radical cation 17a•+, together with the most
+
−
electrophilic Pk Parr function of 10, and the most nucleophilic Pk Parr
function of vinyl ether 17a.
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slightly larger than those at the α carbonyl group, 0.09 at the in complete agreement with the experimental outcomes; (v) as
carbon and 0.04 at the oxygen. Consequently, a larger electron expected, the activation enthalpies associated with the meta
density is accumulated at the β carbonyl group through the TSs, ranging from 18.2 to 22.0 kcal mol−1 (Fig. S1†), are con-
GEDT taking place along this polar process. Therefore, along siderably higher than those associated with the ortho ones, in
the second stage of the reaction, a more favorable electronic complete agreement with the analysis of the Parr functions;
interaction takes place between the electron deficient C6 and finally, (vi) these hetero-Diels–Alder reactions are strongly
carbon of the ethylene framework and the β carbonyl oxygen, exothermic by ca. 33 kcal mol−1
allowing us to explain the origin of the site-selectivity, i.e. pseu- Inclusion of the entropies to the enthalpies increases the
docyclic selectivity,38 found in the hetero-Diels–Alder reaction activation Gibbs free energies by ca. 13 kcal mol−1, and
.
of 10.
decreases the exergonic character of these hetero-Diels–Alder
reactions by 15 kcal mol−1 because of the unfavorable acti-
Study of the polar hetero-Diels–Alder reaction of compounds 5 vation entropies associated with these bimolecular processes
and 10 with ethyl vinyl ether 17a
(see Table S1†). In spite of this, the selectivities are not modi-
fied, the β-endo reaction path being the most favorable one.
Highly polar Diels–Alder reactions involving non-symmetric
reagents take place through highly asynchronous TSs associ-
ated with two-center interactions. Consequently, three stereo-
isomeric TSs associated with the two gauche and the anti
approach modes of the C5 carbon of ethylene 17a and the C6
carbon of heterodiene 10 are feasible. The two pairs of iso-
meric TSs given in Scheme 10 correspond to the gauche confor-
mational approach modes of the C5–C6 double bond of the
vinyl ether 17a to the C1–C2 double bond of the heterodiene
10. Additionally, two anti approach modes are feasible yielding
two zwitterionic intermediates, which must rotate around the
new C1–C5 single bond in order to achieve the formation of
the corresponding cycloadducts (see Fig. S5, Scheme S1 and
Table S1†). Although the activation enthalpies associated with
the anti attacks are only 0.1 (TS1α) and 0.2 (TS1β) kcal mol−1
higher than that associated with TSβ-endo, these energy differ-
ences rise to 1.3 (TS1α) and 1.4 (TS2β) kcal mol−1 at the TSs
associated with the ring-closing step (see Table S1†). In this
polar Diels–Alder reaction the anti reaction paths are some-
what competitive with the gauche ones.
Due to the presence of two heterodiene frameworks at 5, and
the asymmetry of the reagents involved in this hetero-Diels–
Alder reaction, eight competitive reaction paths are possible.
They are related to a pair of regioisomeric reaction paths and a
pair of endo/exo stereoisomeric reaction paths, for the partici-
pation of each of the two heterodiene frameworks. Due to the
total regioselectivity found in polar Diels–Alder reactions, pre-
dicted by the analysis of the Parr functions, only the endo and
exo stereoisomeric reaction paths associated with the for-
mation of the C1(O4)–C5(C6) or C1(O4′)–C5(C6) single bonds
were considered (see Scheme 10).
The activation enthalpies in DCM associated with the four
competitive reaction paths dealing with the hetero-Diels–Alder
reaction of 10 with 17a are: 4.0 (TSα-endo), 4.9 (TSα-exo), 3.1
(TSβ-endo) and 4.3 (TSβ-exo) kcal mol−1, the reaction being
strongly exothermic by 29–33 kcal mol−1 (see Table S1†). Some
appealing conclusions can be drawn from these energy values:
(i) this hetero-Diels–Alder reaction presents a very low acti-
vation enthalpy due to the highly polar character of the reac-
tion; (ii) this activation enthalpy is slightly lower than that
associated with the hetero-Diels–Alder reaction involving com-
pound 5 (see Fig. S2†); (iii) the endo approach modes are less
energetic than the exo ones; (iv) the most favorable reaction
path corresponds to the formation of the cycloadduct β-endo,
The geometries of the four gauche TSs are shown in Fig. 4.
Despite the different geometries derived for the corresponding
Scheme 10 Competitive stereoisomeric reaction paths associated with
the polar hetero-Diels–Alder reaction of 10 with 17a. Relative enthalpies
in kcal mol−1 are given in parentheses, while relative Gibbs free energies
in kcal mol−1 are given in brackets. Thermodynamic data were computed
at 298.15 K in DCM.
Fig. 4 Geometries of the four gauche TSs associated with the hetero-
Diels–Alder reaction of 10 with 17a.
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reactant pairs, coming from the approach of the α- and aryl substituted alkylidene derivatives, thus enabling their iso-
β-heterodienes, the lengths of the C–C and C–O bonds lation and increasing the site-selectivity of their hetero-Diels–
forming at the TSs are of the same order of magnitude for all Alder reactions under mild conditions. The cycloadducts that
modes, ranging from 2.03 to 2.08 Å for the C1–C5 and from derived from the β-heterodiene part resemble the β-lapachone
3.02 to 3.12 Å for the O4(4′)–C6 single bonds. These lengths structure and are the ones that were predominant in most of
indicate that these TSs correspond to the highly asynchronous the reactions. Beyond this, a reversal of the site-selectivity was
single bond formation processes. Analysis of the intrinsic reac- also observed in relation to that of the analogous hetero-Diels–
tion coordinates (IRCs) of the TSs indicates that these polar Alder reactions of the corresponding unprotected derivatives,
hetero-Diels–Alder reactions are associated with a non-con- where the cycloaddition products of the α-heterodiene moiety
certed two-stage one-step mechanism,39 in which the C6–O4 predominated. The yields and the selectivity of the reactions
single bond formation begins when the first C1–C5 single studied were not significantly influenced by the substituents
bond is practically formed. Reactions 5/17a show similar of the heterodiene groups. They were, however, affected by the
results (Fig. S2†).
type of substitution of the individual dienophiles and mainly
The polar character of this hetero-Diels–Alder reaction was by the steric hindrance they introduce.
analyzed by computing the GEDT values at the corresponding
The reactivity of the new dihydrobenzochromenone acetals
TSs. These values at the endo TSs, 0.40e at TSβ-endo and 0.42 was found to be reduced due to the selective protection of
at TSα-endo, point to the highly polar character of this hetero- their most reactive carbonyl group. An application of this
Diels–Alder reaction. This finding is in complete agreement highly selective methodology in the synthesis of new functio-
with the very low computed activation enthalpies.26
nalized quinone derivatives is currently in progress.
DFT calculations were in good agreement with the reactivity
and site-selectivity of the reactions, revealing their polar nature
and the operation of an asynchronous two-stage one-step
mechanism. At the same time, our calculations precluded the
operation of an alternative stepwise mechanism through a suc-
cessive Michael addition/cyclization.
Calculations of other specific polar hetero-Diels–Alder
reactions
The most favourable 14b/17a β-type reaction paths were only
studied, in line with the above results. It was shown that they
exhibit the same characteristics as those of the 10/17a reaction,
being polar Diels–Alder ones, presenting a highly asynchro-
nous mechanism. Moreover, the significant increase of the
energies for these TSs (15.6 kcal mol−1 and 16.8 kcal mol−1, Experimental
for the TSβ-endo and the TSβ-exo, respectively; see also
Table S3†) compared to those of the 10/17a reaction could be
Computational details
Details on the computational method used are given in a
attributed to the significant steric hindrance introduced by the
tolyl group of 14b. It is worth noting here that the 14b/17a
reactions studied are medium exothermic processes; the cyclo-
adducts 29a and 30a are located −24.1 and −21.1 kcal mol−1
below the reagents.
Calculations also showed that the α-endo and β-endo
isomers from the reactions 10/33a and 10/33c afforded higher
corresponding activation energy values (shown in Fig. S3 and
S4,† respectively), than those of reaction 10/17a, which could
be associated with the lower reaction yields derived. Moreover,
the low preference for the endo cycloadducts of the
β-heterodiene group, exhibiting the lowest activation energies
calculated – signifying also its higher electrophilicity with
respect to that of the α-heterodiene group – is in line with the
site-selectivity of the above reactions.
recent paper.25 The B3LYP/6-31G(d) level of theory,40,41 was
used throughout for the study of the stationary points found
in the potential energy surfaces (PES), since it was shown to be
suitable for the analysis of the geometric and electronic pro-
perties of Diels–Alder reactions.42 The determination of the
appropriate TSs connecting reactants and products has been
confirmed by IRC calculations,43 and intrinsic reaction paths
(IRPs) were traced from the various TSs to ensure that no
further intermediates exist. Solvent effects of DCM were con-
sidered using the polarisable continuum model (PCM) devel-
oped by Tomasi’s group.44 Thermodynamic data were com-
puted at 298.15 K in DCM. The GEDT36 at the TSs were ana-
lyzed using the Natural Bond Order (NBO) method.45 CDFT
global reactivity indices and Parr functions were computed
using the equations given in ref. 34. All calculations were
carried out using the Gaussian09 programs suite.46
Conclusions
General information
In this work, we developed a new and efficient method for the All enol ethers and alkenes were commercially available.
synthesis of the 1,1-dimethoxy acetal of lawsone under basic Melting points were measured with a Koffler hot stage and are
conditions. The alkylidene and arylidene derivatives of this uncorrected. 1H and 13C NMR spectra were recorded on a
1
protected lawsone were prepared through Knoevenagel con- Bruker AM 300 (300 MHz for H NMR; 75 MHz for 13C NMR)
1
densation and they possessed two distinct heterodiene (α and or an Agilent Varian 500 (500 MHz for H NMR; 125 MHz for
β) parts that exhibited reduced overall electrophilicity relative 13C NMR), in CDCl3 and quoted relative to tetramethylsilane
to their unprotected analogs. This led to stabilization of the as an internal reference. Mass spectral data were obtained on a
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High Performance Liquid Chromatograph/Mass Spectrometer
(LC-MS) equipped with an ESI interface. Analyses were per-
Conflicts of interest
formed with a PerkinElmer 2400-II analyzer. The reactions There are no conflicts to declare.
under MW irradiation were performed in closed vessels in a
Biotage Initiator 2.0 with an external sensor for measuring
reaction mixture temperatures. Column chromatography was
performed on silica gel (Merck 60, 70–230 Mesh) and analyti-
Notes and references
cal TLC was carried out on precoated silica gel plates (F254,
0.25 mm). Petroleum ether (PE) refers to the fraction 40–60 °C.
1 (a) R. H. Thomson, Naturally Occurring Quinones IV. Recent
Advances, Blackie A&P, London, 1997.
2 A. K. Jordão, M. D. Vargas, A. C. Pinto, F. de C. da Silva and
V. F. Ferreira, RSC Adv., 2015, 5, 67909–67943; and refer-
ences cited therein.
Preparation of 4,4-dimethoxynaphthalene-1,3-dione (12)
A catalytic amount of conc. H2SO4 (two drops) was added to a
hot suspension of lawsone (1000 mg, 5.7 mmol) in acetic anhy-
dride (1.4 mL, 14.4 mmol) and the mixture was heated in an
oil bath for 15 min. Upon addition of water, acetyl lawsone 11
precipitated26 and was collected by filtration. It was thoroughly
washed with water and then dried under vacuum. The crude
ester 11 (1186 mg, 5.49 mmol) was dissolved in methanol
(30 mL) and K2CO3 (2273 mg, 16.47 mmol) was added. After
stirring for 30 min at rt, potassium carbonate was removed by
filtration and the filtrate was concentrated in a rotary evapor-
ator. The resulting mixture was carefully neutralized with a
dilute hydrochloric acid solution and then was extracted with
CH2Cl2 (3 × 20 mL) and washed with brine. The organic layer
was dried (Na2SO4) and concentrated to afford the acetal 12 in
78% total yield (983 mg, 4.47 mmol).
3 (a) J. S. Sun, A. H. Geiser and B. Frydman, Tetrahedron Lett.,
1998, 39, 8221–8224; (b) G. Kazantzi, E. Malamidou-
Xenikaki and S. Spyroudis, Synlett, 2007, 427–430.
4 K. D. Barange, V. Kavala, B. R. Raju, C.-W. Kuo, C. Tseng
and Y.-C. Tu, Tetrahedron Lett., 2009, 50, 5116–5119.
5 E. Malamidou-Xenikaki and S. Spyroudis, Synlett, 2008,
2725–2740.
6 G. Kazantzi, E. Malamidou-Xenikaki and S. Spyroudis,
Synlett, 2006, 2597–2600.
7 S. Koulouri, E. Malamidou-Xenikaki, S. Spyroudis and
M. Tsanakopoulou, J. Org. Chem., 2005, 70, 8780–8784.
8 E. Glinis, E. Malamidou-Xenikaki, H. Skouros, S. Spyroudis
and M. Tsanakopoulou, Tetrahedron, 2010, 66, 5786–5792.
9 E.
Malamidou-Xenikaki,
M.
Tsanakopoulou,
M. Chatzistefanou and D. Hadjipavlou-Litina, Tetrahedron,
2015, 71, 5650–5661.
10 A. R. Burnett and R. H. Thomson, J. Chem. Soc. C, 1967,
2100–2104.
11 Y. Li, X. Sun, J. T. LaMont, A. B. Pardee and C. J. Li, Proc.
Natl. Acad. Sci. U. S. A., 2003, 100, 2674–2678.
Preparation of arylidene-4,4-dimethoxynaphthalene-1,3-diones
14a–d
General procedure. In a solution of the acetal 12 (40 mg,
0.18 mmol) in CH2Cl2 (3 mL) the appropriate aldehyde 13 12 N. E. Mealy and B. Lupone, Drugs Future, 2006, 31, 627–639.
(0.36 mmol), anhydrous MgSO4 (65 mg, 0.54 mmol) and a 13 (a) S. C. Hooker, J. Am. Chem. Soc., 1936, 58, 1181;
catalytic amount of S-proline (4 mg, 0.036 mmol) were added
and the mixture was stirred for 2 days at rt. MgSO4 was
removed by filtration and the filtrate was concentrated and
(b) K. Schaffner-Sabba, K. H. Schmidt-Ruppin, N. Wehrli,
A. R. Schurch and J. W. Wasley, J. Med. Chem., 1984, 27,
990; and references cited therein.
subjected to column chromatography (silica gel, PE/ethyl 14 C. Salas, R. A. Tapia, K. Ciudad, V. Armstrong, M. Orellana,
acetate 5 : 1) to afford the unreacted aldehyde and products 14
in order of elution. The arylidene-1,3-diones 14 were crystal-
lized upon trituration with mixtures of PE/Et2O.
U. Kemmerling, J. Ferreira, J. D. Maya and A. Morello,
Bioorg. Med. Chem., 2008, 16, 668–674.
15 R. Cassis, R. Tapia and J. A. Valderrama, J. Heterocycl.
Chem., 1984, 21, 865–868.
16 (a) V. F. Ferreira, A. V. Pinto and L. C. M. Coutada, An. Acad.
Bras. Cienc., 1980, 52, 477–479; (b) A. B. de Oliveira,
D. T. Ferreira and D. S. Raslan, Tetrahedron Lett., 1988, 29,
155–158; (c) Y. R. Lee, J. H. Choi, D. T. L. Trinh and
N. W. Kim, Synthesis, 2005, 3026; (d) Y. R. Lee and
W. K. Lee, Synth. Commun., 2004, 34, 4537.
General procedure for the reactions of acetal 12 with
formaldehyde and vinyl ethers 17
Synthesis of the 4-aryl-dihydrobenzochromenones 18, 19, 22
and 23. A solution of the acetal 12 (60 mg, 0.27 mmol) in
CH3CN (6 mL) was placed in an ice bath. Aqueous formal-
dehyde 37% (0.05 mL), anhydrous MgSO4 (97.5 mg, 17 R. Inagaki, M. Ninomiya, K. Tanaka and M. Koketsu,
0.814 mmol) and a catalytic amount of S-proline (6 mg, ChemMedChem, 2015, 10, 1413–1423.
0.054 mmol) were added and the mixture was stirred for 18 (a) Y. Gao, Q. Ren, S.-M. Ang and J. Wang, Org. Biomol.
30 min. An excess of the appropriate vinyl ether 17 was added
and the mixture was kept at rt overnight. MgSO4 was removed
Chem., 2011, 9, 3691–3697; (b) M. Rueping, E. Sugiono and
E. Merino, Angew. Chem., Int. Ed., 2008, 47, 3046–3049.
by filtration and the filtrate was subjected to column chrom- 19 V. Nair and P. M. Treesa, Tetrahedron Lett., 2001, 42, 4549.
atography (silica gel, PE/ethyl acetate 7 : 1) to afford the di- 20 D.-Q. Peng, Y. Liu, Z.-F. Lu, Y.-M. Shen and J.-H. Xu,
hydrobenzochromenones 18, 19, 22 and 23.
Synthesis, 2008, 1182–1192.
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21 V. F. Ferreira, S. B. Ferreira and F. de C. da Silva, Org. 33 L. R. Domingo, E. Chamorro and P. Pérez, J. Org. Chem.,
Biomol. Chem., 2010, 8, 4793–4802. 2008, 73, 4615–4624.
22 F. de C. da Silva, S. B. Ferreira, C. R. Kaiser, A. C. Pinto and 34 L. R. Domingo, M. Ríos-Gutiérrez and P. Pérez, Molecules,
V. F. Ferreira, J. Braz. Chem. Soc., 2009, 20, 1478–1482. 2016, 21, 748.
23 S. Jiménez-Alonso, H. C. Orellana, A. Estévez-Braun, 35 R. G. Parr and R. G. Pearson, J. Am. Chem. Soc., 1983, 105,
A. G. Ravelo, E. Pérez-Sacau and F. Machín, J. Med. Chem.,
2008, 51, 6761–6772.
7512–7516.
36 L. R. Domingo, RSC Adv., 2014, 4, 32415–32428.
24 L. R. Domingo, M. T. Piche and P. Arroyo, Eur. J. Org. 37 L. R. Domingo, P. Pérez and J. A. Sáez, RSC Adv., 2013, 3,
Chem., 2006, 2570–2580. 1486–1494.
25 E. Malamidou-Xenikaki, S. Spyroudis, E. Tsovaltzi and 38 L. R. Domingo, M. Ríos-Gutiérrez and P. Pérez, Molecules,
E. G. Bakalbassis, J. Org. Chem., 2016, 81, 2383–2398. 2018, 23, 1913.
26 L. R. Domingo and J. A. Sáez, Org. Biomol. Chem., 2009, 39 L. R. Domingo, J. A. Saéz, R. J. Zaragozá and M. Arnó,
3576–3583. J. Org. Chem., 2008, 73, 8791–8799.
27 (a) L. A. Cort and P. A. B. Rodriguez, J. Chem. Soc. C, 1967, 40 (a) A. D. Becke, J. Chem. Phys., 1993, 98, 5648–5652;
949–952; (b) R. B. Smith, C. Canton, N. S. Lawrence,
C. Livingstone and J. Davis, New J. Chem., 2006, 30, 1718–1724.
(b) C. Lee, W. Yang and R. G. Parr, Phys. Rev. B: Condens.
Matter Mater. Phys., 1988, 37, 785–789.
28 J. L. Marshall, Carbon-Carbon and Carbon-Proton NMR 41 W. J. Hehre, L. Radom, P. v. R. Schleyer and J. A. Pople,
Couplings; Application to Organic Stereochemistry and
Conformational Analysis, Chemie, Deerfield Beach, Florida,
USA, 1983, pp. 33–42.
Ab initio Molecular Orbital Theory, Wiley, New York,
1986.
42 D. H. Ess, G. O. Jones and K. N. Houk, Adv. Synth. Catal.,
2006, 348, 2337–2361.
29 B. Neochoritis, N. Eleftheriadis, C. Tsoleridis and
J. Stephanidou-Stephanatou, Tetrahedron, 2010, 66, 709–714. 43 K. Fukui, J. Phys. Chem., 1970, 74, 4161–4163.
30 C. List, R. A. Lerner and C. F. Barbas, J. Am. Chem. Soc., 44 J. Tomasi and M. Persico, Chem. Rev., 1994, 94, 2027–
2000, 122, 2395–2396.
31 S. B. Ferreira, K. Salomão, F. de C. da Silva, A. V. Pinto, 45 (a) A. E. Reed, R. B. Weinstock and F. Weinhold, J. Chem.
2094.
C. R. Kaiser, A. C. Pinto, A. V. Pinto, V. F. Ferreira and
S. L. de Castro, Eur. J. Med. Chem., 2011, 46, 3071–3077.
Phys., 1985, 83, 735–746; (b) A. E. Reed, L. A. Curtiss and
F. Weinhold, Chem. Rev., 1988, 88, 899–926.
32 R. G. Parr, L. von Szentpaly and S. Liu, J. Am. Chem. Soc., 46 M. J. T. Frisch, et al., Gaussian 09, Revision B.01, Gaussian,
1999, 121, 1922–1924.
Inc., Wallingford, CT, 2010.
702 | Org. Biomol. Chem., 2019, 17, 692–702
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