Intercepted-Knoevenagel condensation for the synthesis of unsymmetrical fused-tricyclic 4H-pyrans

Article abstract of DOI:10.1016/j.tet.2019.130606

4H-Pyrans (4H-Pys) and 1,4-dihydropyridines (1,4-DHPs) are important classes of heterocyclic scaffolds in medicinal chemistry. Herein, an indium(III)-catalyzed one-pot domino reaction for the synthesis of highly functionalized 4H-Pys, and a model of 1,4-D

Full text of DOI:10.1016/j.tet.2019.130606

Tetrahedron 75 (2019) 130606
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Tetrahedron
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Intercepted-Knoevenagel condensation for the synthesis of
unsymmetrical fused-tricyclic 4H-pyrans
Charles Shearer, Oriane Desaunay, Stephen Zorc, Alexis D. Richaud, Shyam S. Samanta,
*
ꢀ
Nagalakshmi Jeedimalla, Stephane P. Roche
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL 33431, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2019
Received in revised form
9 September 2019
Accepted 11 September 2019
Available online 17 September 2019
4H-Pyrans (4H-Pys) and 1,4-dihydropyridines (1,4-DHPs) are important classes of heterocyclic scaffolds
in medicinal chemistry. Herein, an indium(III)-catalyzed one-pot domino reaction for the synthesis of
highly functionalized 4H-Pys, and a model of 1,4-DHP is reported. This alternative approach to the
challenging Hantzsch 4-component reaction enables the synthesis of fused-tricyclic heterocycles, and
the mechanistic studies underline the importance of an intercepted-Knoevenagel adduct to achieve
higher chemoselectivity towards these types of unsymmetrical heterocycles.
Published by Elsevier Ltd.
Keywords:
Intercepted-Knoevenagel condensation
Multicomponent reaction
4H-pyrans
Domino reaction
Hydrogen-bond network
1. Introduction
such as the fused tricyclic 1,4-dihydropyridine skeleton 3 (Fig. 1).
Multicomponent reactions (MCRs) are enjoying a prominent
Etoposide (Vepesid®), a synthetic glycosylated derivative from
the heterolignan natural product podophyllotoxin, is commonly
used in cancer chemotherapy [1]. Other analogs such as the 4-aza-
podophyllotoxins 1 have also shown important biological activity
as antimitotic and vascular-disrupting agents (Fig. 1). We recently
reported the synthesis of a library of potent 4-aza-podophyllotox-
ins from which several hits have emerged with a selective biolog-
ical activity profile against leukemia [2]. While the cytotoxicity of
the dihydroquinoline (DHQ) chemotype 1 has been underlined in
several other biological screenings (Servier, NCI-60) for the devel-
opment of potent antimitotic compounds, the current synthetic
ability to diversify this portfolio of heterocycles is limited [3].
status in modern organic synthesis because they are amenable to
snapping together multiple starting materials (components) into a
complex molecule with outstanding atom economy in a single pot.
MCRs are therefore ideal transformations to quickly generate
architecturally, and functionally, diverse scaffolds for screening
purposes in medicinal chemistry [6]. MCRs can only be practical and
efficient if each partner has a specific reactivity, and plays an unam-
biguous role to react with the other components in a perfectly
orchestrated fashion towards a single product. This dogma suggests
that components with similar functional groups cannot effectively
participate in a MCR without nurturing a problem of chemo-
selectivity, ultimately leading to undesirable competitive reaction
pathways. For instance, the synthesis of the DHQs 1 is typically
achieved via a 3-component reaction, the Husson-3CR, between an
aniline 4, an aldehyde 5 and tetronic acid 6 (Scheme 1) [7]. Simi-
larly, the Hantzsch-3CR is also a well-established MCR for the
synthesis of symmetrical 1,4-dihydropyridines (1,4-DHPs) [8]. On
the other hand, the efficiency and the scope of the Hantzsch-4CR
towards unsymmetrical 1,4-DHP products 9 is extremely limited
[9]. Seemingly, all published Hantzsch-4CRs showcase the specific
use of a cyclic 1,3-dicarbonyl (e.g. 10) with an acyclic alkyl acetoa-
cetate partner. The issue of chemoselectivity between components
highlights the challenge in expanding the scope of this MCR which
Interestingly,
some
closely
related
heterocycles,
1,4-
dihydropyridines (1,4-DHPs), proved to be excellent scaffolds to
advance L-type calcium channel blockers [4] which are used clini-
cally to treat hypertension (e.g. amlodipine 2, barnidipine and other
members of the “edipine” family) [5]. Given the significant bio-
activities of both chemotypes 1 and 2, we were drawn to synthesize
novel analogs built on a hybrid scaffold between DHQ and 1,4-DHP
* Corresponding author.
E-mail address: sroche2@fau.edu (S.P. Roche).
https://doi.org/10.1016/j.tet.2019.130606
0040-4020/Published by Elsevier Ltd.

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C. Shearer et al. / Tetrahedron 75 (2019) 130606
Hantzsch-4CR engaging two distinct, but reactively comparable
cyclic 1,3-dicarbonyls such as tetronic acid 6, and dimedone 10 may
promote several competitive pathways. As model reaction, we
examined the synthesis of fused-tricyclic dihydropyridine 9a in a
racemic form, through the screening of established reaction con-
ditions (Table 1) [9,13]. To identify a potential catalyst(s) that will
promote an unbiased chemoselective Hantzsch-4CR orchestration,
ratios between all components p-nitrobenzaldehyde 5a, tetronic
acid 6, dimedone 10, and ammonium acetate were mainly kept
equimolar (Table 1). Surprisingly, none of the conditions previously
reported for Hantzsch-4CRs afforded any traces of the anticipated
1,4-DHP product 9a. Instead, a mixture of pseudo-symmetrical
dienols 13a and 14a [14] along with the unsymmetrical dienol 12a
were obtained uncyclized, without any evidence of nitrogen
incorporation [15]. Secondly, only the unsymmetrical dienol 12a
was found to spontaneously cyclize during the purification on
(neutralized and anhydrous) silica gel or on alumina chromatog-
raphy which further rendered the crude reactions' characterization
difficult. As previously stated by Sun, we found that dienol 12a
Fig. 1. Biologically active chemotypes of interest.
(benzylic proton
corresponding 4H-pyran 11a (benzylic proton
d
5.71 ppm) transformed spontaneously into the
5.61 ppm) on silica
d
gel, or during any acidic workup (Fig. 2) [16b]. On the contrary,
pseudo-symmetrical dienols 13a and 14a are highly stable and can
be smoothly isolated (vide infra for a discussion about dienol sta-
bilization by an intramolecular hydrogen-bond network). As shown
in Table 1, dienol 12a (isolated as 11a) was obtained as the major
product in most reactions, but significant amounts of pseudo-
symmetrical homodimers 13a and 14a were also generated. For
instance, upon simple grinding of the 4-components neat, 11a was
isolated in 27% yield (entry 1) [9f]. Based off literature precedents,
several reactions were evaluated in ethanol, in presence of either
iodine [9a], cerium ammonium nitrate (CAN) as a catalyst [9c], or
with a montmorillonite clay [9l] (entries 2e5). In comparison to the
control experiment in pure ethanol (entry 2), the clay seems to have
little effect on the course of the reaction and yielded the desired
product 11a in 50% yield (entry 3). In contrast, the catalytic activity
of CAN has a more drastic effect on the ratio of products (no
dimedone dimer 13a observed), while accelerating the reaction
rate to afford 11a in only 30 min and 40% yield (entry 5). Using
either ytterbium or scandium triflates, as Lewis acid catalysts,
product 11a was isolated in surprisingly modest yields 14% and 33%
respectively (entries 6e7). [9b,9j] Acetoacetates are known bidentate
ligands for Ru(III) metal, therefore a reaction with 1 mol% of RuCl3
Lewis acid was tested (entry 8). Under these conditions, the tetronic
dimer 14a became the main product of the reaction, which likely
indicates that a 3CR takes place around the metal center with the
tetronic acid ligand henceforth extruding the dimedone partner 10
from the reaction. Given the result with CAN (entry 5), which could
likely proceed through a single-electron oxidation mechanism of
the 1,3-dicarbonyl, reactions with Ru(BPy)3Cl2 under blue LEDs
visible-light irradiation or in the dark were attempted (entry 9),
and remarkably afforded the tetronic dimer 14a as the main
product (53% NMR yield).[9m] Finally, indium trichloride was also
tested to catalyze this reaction in two different solvents (entries
10e11), and product 11a was preferentially synthesized in ethanol
in 44% isolated yield. 1H NMR spectroscopy monitoring of the
Hantzsch-4CR suggested that the major pathway might arise from a
Knoevenagel adduct en route to the corresponding dienols prod-
ucts 12a, 13a, and 14a, which is in agreement with the results ob-
tained by Sinha from mass spectrometry studies (ESI-MS/MS) [17].
These results might well explain why mostly biased examples of
Hantzsch-4CR have been reported [9]. Taken together, these pre-
liminary results suggest that CAN and InCl3 are the most efficient
catalysts to synthesize the 4H-pyran 11a in a multicomponent
fashion, and that further optimizations will be require in order to
Scheme 1. Multicomponent reaction strategies towards 1,4- dihydroquinoline 1 and
dihydropyridine 2 scaffolds.
led to the development of numerous creative solutions, typically
with two of the components condensed separately prior to being
engaged into a Hantzsch-3CR (e.g.
b-enamino ketone 7 or Knoe-
venagel adduct 8, Scheme 1) [10,11].
Despite the recent advances in diastereoselective and enantio-
selective variants of the Hantzsch-3CR, the synthesis of unsym-
metrical 1,4-DHPs
9
remains challenging [10]. Therefore,
developing a Hantzsch-4CR (or a one-pot alternative) to synthesize
complex fused-tricyclic 1,4-dihydropyridines [12] is an exciting
endeavor that would require the discovery of a novel strategy to
timely or chemoselectively introduce two, similarly reactive, cyclic
1,3-dicarbonyl partners. Based on unexpected results for the
Hantzsch-4CR reported herein, a mechanistic-based rationale is
advanced to prepare unsymmetrical fused-tricyclic 4H-pyran (4H-
Py) 11, and their 1,4-DHPs 9 counterparts. This primed us to opti-
mize a novel domino one-pot protocol that takes advantage of an
intercepted Knoevenagel condensation to access these unsym-
metrical heterocycles 9/11 which could not be obtained via a direct
MCR.
2. Results and discussion
2.1. Attempts of a Hantzsch-4CR for the synthesis of fused-tricyclic
1,4-dihydropyridines
As mentioned in the scenario above, we anticipated that a

C. Shearer et al. / Tetrahedron 75 (2019) 130606
3
Table 1
Attempted Hantzsch-4CR toward fused-tricyclic dihydropyridine 9a.
Entry
Component ratio
Promoter
Solvent Time
Crude % -ratioa
% Yield (11a)b
10
5a
6
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
ec
2 h
6 (8%); 12a (39%) 13a (25%); 14a (27%)
6 (0%); 12a (52%) 13a (17%); 14a (20%)
6 (5%); 12a (51%) 13a (24%); 14a (20%)
6 (8%); 12a (26%) 13a (15%); 14a (23%)
6 (11%); 12a (54%) 13a (0%); 14a (18%)
6 (4%); 12a (24%) 13a (0%); 14a (12%)
6 (4%); 12a (24%) 13a (0%); 14a (15%)
6 (0%); 12a (27%) 13a (26%); 14a (47%)
6 (0%); 12a (33%) 13a (14%); 14a (53%)
6 (0%); 12a (35%) 13a (17%); 14a (38%)
6 (0%); 12a (50%) 13a (15%); 14a (28%)
27
40
50
11
40
14
33
e
EtOH, 18 h
EtOH, 18 h
EtOH, 3 h
EtOH, 25min
CH3CN, 4 h
CH3CN, 4 h
CH3CN, 3 h
CH3CN, 3 h
CH3CN, 5 h
EtOH, 20 h
montmorillonite (750 mg)
l2 (30 mol%)
1
CAN (5 mol %)
Yb (OTf)3 (10 mol%)
Sc(OTf)3(10 mol%)
RuCl3 (1 mol %)
Ru(BPy)3Cl2 (1 mol%)d
lnCl3 (10 mol%)
lnCl3 (10 mol%)
1.5
1.5
1
1
1
n.de
n.d.
n.d.
44
9
10
11
1
a
Reactions were conducted on 1.0 mmol of NH4OAc at room temperature and %-ratios were calculated from crude 1H NMR using signals indicated on the schematic
(benzylic protons chemical shifts reported are in CD3OD).
b
Due to the unavoidable transformation of 12a into 11a on silica gel, the isolated yields of analytically pure product 11a are reported.
Reaction promoted by grinding the 4 components neat.
Similar results were obtained under blue LED-irradiation or in the dark as control which demonstrates that no visible-light photocatalysis is taking place.
The reaction yield was not determined because the major product was the undesired homodimer 14a.
c
d
e
Fig. 2. Isolated Product 11a from the attempted Hantzsch-4CR.
synthesize unsymmetrical 1,4-DHP products (e.g. 9a) [18].
2.2. Discovery and reactivity of the Intercepted-Knoevenagel adduct
16 towards unsymmetrical products
To further probe the mechanism of this multicomponent reac-
Scheme 2. Role of the Knoevenagel condensation adduct 15 toward unsymmetrical
homo- and heterodimers 13a/12a.a.
tione which did not incorporate ammoniae we studied reactions of
p-nitrobenzaldehyde 5a with tetronic acid 6 and dimedone 10
separately. It was found that 10 reacts more rapidly with 5a to
deliver the pseudo-symmetrical homodimer 13a (Scheme 2). This
reaction was found to be cleaner and faster upon the addition of a
catalytic amount of pyrrolidine leading ultimately to the formation
of 13a in 50% yield. The expected Knoevenagel adduct 15 was not
observed which lead us to postulate that the two ketones flanking
the alkylidene moiety enhanced its reactivity, thus triggering a
spontaneously 1,4-addition of a second dimedone molecule, hence
the formation of 13a as the sole product of the reaction [16].
Therefore, we hypothesized that a stable alkylidene surrogate of 15,
such as the Mannich-base 16, could solve this issue of chemo-
selectivity via a stepwise approach. Bolte and others reported that
Knoevenagel products could be intercepted by secondary amines to
form stable Mannich bases [19], therefore we reasoned that such
product 16 could be utilized for the synthesis of unsymmetrical
heterocycles. Indeed we found that InCl3 efficiently catalyzed the
condensation between 10 and 5a, while the Knoevenagel
intermediate 15 was intercepted with pyrrolidine to afford the
adduct 16 in 88% isolated yield [20]. As shown by Porco Jr. and
others, pyrolidine adducts such as.16 are stable and potential in situ
precursors of Knoevenagel alkylidenes [21]. Directly treating 16
with the pro-nucleophile tetronic acid 6 enabled the clean forma-
tion of the unsymmetrical dienol adduct 12a in 85% yield. In this
event, we propose that tetronic acid 6 (pKa(H2O) ~3.8) favorably
protonates the pyrrolidine nitrogen of 16, triggering the leaving
group extrusion while transforming the pro-nucleophile 6 into a
more reactive conjugated enolate for the ensuing 1,4-addition.
Using this strategy, the unsymmetrical open-dienol product 12a
was obtained in 75% yield over 2 steps (Scheme 2).
The intercepted Knoevenagel condensatione1,4-addition
sequence was further optimized to synthesize the pseudo-sym-
metrical dienol 12a in one-pot (Table 2). Given that InCl3 was

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C. Shearer et al. / Tetrahedron 75 (2019) 130606
Table 2
Optimization for the synthesis of unsymmetrical dienol 12a via the interrupted
Knoevenagel pyrolidine adduct 16.
Entry
Solventa
Time
% Conv.b
% Yieldb
Step 1
Step 2
1
Toluene-d8
CH3CN
CH3CN
CD3CD
DMSO‑d6
DMSO
3 h
2 h
4 h
3 h
2 h
5 h
12 h
30 min
1 h
2 h
20 min
1 h
60
92
99
94
100
96
55
68
75
65
90
88
2
3c
4
5
6c
a
Reactions were conducted on 1.0 mmol scale of 10, 5, 6 with pyrrolidine (1.0 eq.)
at room temperature, using InCl3 (10 mol%) unless otherwise stated.
b
Conversions and yields were calculated from crude 1H NMR using mesitylene as
internal standard.
c
Reaction carried out without InCl3.
initially one of the best catalysts for the MCR (see Table 1, entries
10e11), this catalyst was selected for reaction optimization. The
one-pot sequence could be carried out in deuterated solvents to
facilitate reaction advancement monitoring by in situ 1H NMR
spectroscopy (for the full Table, see Supporting Information
Tables SIe1). While the 2-step reaction was low yielding in toluene-
d8 (entry 1), reactions in CH3CN, CD3OD and DMSO‑d6 were clean,
and delivered 12a in less than 6 h. Without catalyst (entries 3 & 6),
the reactions still proceeded to completion and delivered 12a in
good yields despite longer reaction times. Overall, the reaction
appeared to be cleaner and faster in DMSO‑d6 and in CH3CN; the
latter solvent was selected to further study the reaction scope due
to an easier work-up with HCl (0.5 M) affording directly the fused
tricyclic 4H-pyran 11a.
Scheme 3. Reaction scope in the synthesis of fused-tricyclic 4H-Pyrans 11.
ray crystal structure obtained by the Sun's group revealed that both
intramolecular hydrogen-bonds are relatively strong as shown by
the bond lengths (~1.80 Å), and the donor-acceptor characteristic
bond angles (close to 180ꢀ) (Fig. 3A).
2.4. NMR and synthetic studies underlining the strength of the
dienol intramolecular hydrogen-bond network
To further characterize this donor-acceptor pair of hydrogen
bonds connected by a resonant
p
ꢁsystem (resonance-assisted
hydrogen bonding: RAHB) [22], a careful 1H NMR spectral analysis
was performed (Fig. 3B/3C) [13]. At ꢁ30 ꢀC, the NMR spectra of 13a
in CDCl3 revealed the presence of two distinct signals corre-
sponding to a strong and a weaker hydrogen bond (OH-1 and OH-2)
2.3. Synthesis of a library of 4H-pyrans 11
With an optimum set of conditions in hand, the scope of the
one-pot reaction catalyzed by InCl3 in acetonitrile was examined
(Scheme 3). A simple acidic work-up at the end of the reactions
enabled the final cyclization for the preparation of 4H-pyrans 11a
and 11c-m in moderate to good yields. The domino reactions pro-
ceeded smoothly with variously substituted benzaldehydes bearing
electron withdrawing groups leading to various 4H-pyrans (e.g. 11a,
11c-d, 11g) in high yields. Reactions with less reactive benzalde-
hydes (with electron neutral and electron donating groups) pro-
duced the desired products (e.g. 11i-m) despite in lower yields. For
the most electron-rich aldehyde the reaction delivered products 11l
and 11m in modest yields (21% and 32% yields respectively); Even
though we have no current explanations for these results, the re-
actions can be improved without indium catalysts to obtain 11l and
11m in 51% and 69% yields (Scheme 3). The reaction was found to
tolerate not only dimedone, but also cyclohexanedione in ring A,
and the thiotetronic acid in ring C, without major differences in
yields (11e vs 11f, and 11g). Compound 12b, similarly to homo-
dimer 13a, is the only substrate from the library which did not
cyclize spontaneously during either acidic workup, or column
chromatography. Accordingly to the report by Sun [16], some
dimeric dienols are remarkably stable due to their intramolecular
at
d 11.91 ppm and 11.78 ppm, as shown by the narrow and larger
peak widths at half-height characterizing their exchange rates (Dy1/
5.59 and 13.86 Hz respectively), which are in agreement with
2
previous reports on similar intramolecular RAHB network of enols
(Fig. 3B) [23]. In stark contrast, dienol 12a presented only one broad
signal accounting for the 2 enolic protons (OH-3), significantly
deshielded (d 9.40 ppm) with a larger peak width at half-height
Dy1/2 of 19.17 Hz typical of a fast equilibrium between rotational
conformers resulting from a weaker hydrogen-bond network.
Variable-temperature 1H NMR studies were further performed to
determine the chemical shift deviation and the melting tempera-
ture for 12a and 13a (Fig. 3C) [24]. As shown in this graph, the
temperature dependence coefficients of three enolic hydroxyl
protons (Dd/T: slopes of linear regressions) were obtained at 25 mM
concentrations in a range of temperatures from ꢁ50 ꢀC to 70 ꢀC for
OH-1 (▪, ꢁ1.9 ppb/K), OH-2 (A, ꢁ3.7 ppb/K) of 12a, and OH-3 (:,
2.1 ppb/K) of 13a. These results suggest that in the range of tem-
peratures studied, the OH chemical shifts are minimally affected as
expected for moderately strong intramolecular hydrogen bonds
(Dd/T < 4 ppb/K) [25]. While examining the temperature de-
pendency on the enolic chemical shifts in CDCl3, it was found that
hydrogen-bond network across the two
b
-diketone enols. The X-
the enolic signal OH-3 for 12a slowly disappeared upon

C. Shearer et al. / Tetrahedron 75 (2019) 130606
5
Scheme 4. Endgame for the synthesis of the unsymmetrical 1,4-dihydropyridine 9a.
the annulation reaction at 105 ꢀC. As suggested above, the high
temperature is required to cleave the hydrogen-bond network and
enable the final cyclization. From this domino one-pot reaction, the
desired 1,4-DHP product 9a was ultimately obtained in 50% yield.
To conclude this study, 4H-Py 11a was also subjected to the annu-
lation conditions, and once again product 9a could be prepared this
time in 63% yield. In this case, 4H-Py 11a might undergo ring
opening before the final cyclization and extrusion of water through
an addition-elimination mechanism.
3. Conclusion
In summary, we reported a general and straightforward one-pot
synthesis of various fused-tricyclic unsymmetrical 4H-pyrans 11.
Indium trichloride has emerged from this study to be the most
efficient catalyst to promote the domino reaction. The mechanistic
and NMR studies revealed two important features to achieve the
domino process: a) the critical role of the intercepted-Knoevenagel
adduct 16 to achieve high chemoselectivity towards these un-
symmetrical heterocycles and b) the importance of the hydrogen-
bonds strength in the network of hydrogen-bonded dienol in-
termediates (e.g. 12a, 13a) which tempered the ease of annulation.
According to the 1H VT-NMR experiments, we found that the
intramolecular hydrogen-bond network of the most symmetrical
Fig. 3. Intramolecular hydrogen-bond strength observed by 1H NMR for pseudo- and
un-symmetrical dienols 13a and 12a.
temperature increase [25a]. The melting temperature (Tm) corre-
sponding to the rupture of the hydrogen-bond network between
dienol conformers in 12a was found to be 50 5 ꢀC, corresponding
dienols are tighter and stronger (D
Gǂ 17.5 0.5 kcal/mol), than the
to
D
a
relatively
low
transition-state
energy
barrier
network in unsymmetrical compounds (DDGǂ ~ 2 kcal/mol) which
could explain the facile synthesis of unsymmetrical 4H-pyrans 11.
For the most symmetrical molecules, the final annulation is
hampered by an intramolecular network of hydrogen bonds be-
tween enols, which can be ruptured at high temperature as sug-
gested by the transition state energy barrier determined by the VT-
NMR experiments. Even though the intercepted-Knoevenagel
condensation with secondary amines has been known for a long
time [19], the ability of such Mannich base 16 to slowly generate
Michael acceptors in situ has been largely ignored. This concept
offers far-reaching opportunities for the synthesis of unsymmetri-
cal and complex 1,4-dihydropyrines such as 9a, which are “privi-
leged structures” in medicinal chemistry [28]. Ongoing studies in
our laboratory aim at developing the scope of this domino reaction,
an alternative strategy to the Hantzsch-4CR, and an asymmetric
variant for the synthesis of fused-tricyclic 1,4-dihydropyridines
[29].
Gǂ ¼ 15.1 0.3 kcal/mol [26]. On the other hand, the melting
temperature of 13a could not be determined in CDCl3
(Tm > 70 5 ꢀC), but the corresponding
D
Gǂ of H-bonds cleavage
was determined to be significantly larger by ~2 kcal/mol
(D
Gǂ ¼ 17.5 0.5 kcal/mol).
These calculations are found to be in general agreement with
the reported stabilities of intramolecular RAHB networks which
might be rationalized by the fact that both enols forming the
p-
resonance-assisted network have similar dipole moments due to
the locked W-configuration of the conjugated cyclic enols [27].
Taken together, these calculations and spectroscopic data suggest
that the pseudo-symmetrical dienol 13a (e.g. 12b, 14a) possess a
stronger and tighter intramolecular hydrogen-bond network that
restricts free rotation around the benzylic CeC bond, which in turn
might hamper the final dehydrative cyclization.
Given that the dienol moieties in 12a can be considered as
vinylogous acid and carbonate with weaker intramolecular in-
teractions, we thought to attempt the final annulation reaction
promoted by a BrØnsted acid with ammonium acetate as the source
of ammonia at a higher temperature (Scheme 4). Compound 12a
was obtained using the domino reaction via the Knoevenagel-
intercepted adduct 16, further evaporated and engaged directly in
4. Experimental
4.1. General information
Reactions were performed in flame-dried glassware under a

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C. Shearer et al. / Tetrahedron 75 (2019) 130606
positive pressure of argon. Yields refer to spectroscopically pure
compounds. Analytical TLC was performed on 0.25 mm glass
backed 60 Å F-254 TLC plates (Silicycle, Inc.). The plates were
visualized by exposure to UV light (254 nm) and developed by a
solution of vanillin in ethanol/sulfuric acid or cerium-ammonium-
molybdate in water/sulfuric acid and heat. Flash chromatography
purifications were performed using 200e400 mesh silica gels
(Silicycle, Inc.). Infrared spectra were recorded on a Nicolet IS5 FT-
IR spectrophotometer. 1H NMR spectra were recorded on a Varian
Mercury400 and a Bruker biospinGmbH (400 MHz) spectrometer
and are reported in ppm using solvent as an internal standard
(CDCl3 at 7.26 ppm, CD3OD at 3.31 ppm and DMSO‑d6 at 2.50 ppm).
NMR spectra were performed using standard parameter and data
are reported as: (b ¼ broad, s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, m ¼ multiplet; coupling constant(s) in Hz, integration).
13C NMR spectra were recorded on a Varian Mercury400 (100 MHz)
spectrometer. Chemical shifts are reported in ppm, with solvent
resonance employed as the internal standard (CDCl3 at 77.2 ppm,
CD3OD at 49.0 ppm and DMSO‑d6 at 39.5 ppm). Melting points
were determined using a Digimelt digital melting point apparatus.
Electron ionization (EI) source was used and Restek (Rtx®-5)
capillary column with 30 m length, 1.25 mm internal diameter and
4.1.2. 3,3,6,6-Tetramethyl-9-(4-nitrophenyl)-3,4,6,7,9,10-
hexahydroacridine-1,8(2H,5H)-dione 13a
In a flame dried round bottom flask, a mixture of p-nitro-
benzaldehyde 5a (76 mg, 0.50 mmol,1.0 eq.), dimedone 10 (140 mg,
1.0 mmol, 2.0 eq.) and ammonium acetate (39 mg, 0.50 mmol, 1.0
eq.) in ethanol (2.5 mL, 0.20 M) were stirred for a day at room
temperature. The white precipitate was then filtered and washed
with ethyl acetate (10 mL) and dry under high vacuum to obtain 13a
in a pure form (176 mg, 0.42 mmol, 85% yield). Rf¼0.49 (EtOAc/
hexanes 30:70). IR
1251, 967,820 cmꢁ1
J ¼ 8.5 Hz, 2H), 7.27 (d, J ¼ 8.5 Hz, 2H), 6.32 (s, 1H), 2.26 (s, 8H), 1.08
(s, 12H). 13C NMR (100 MHz, CD3OD):
(ppm) 191.2 (4C), 154.7,
n
.
max (neat): 3410, 3064, 2960, 1591, 1451, 1374,
1H NMR (400 MHz, CD3OD):
d
(ppm) 8.02 (d,
0.1 mm film thickness. Accurate mass spectra (HRMS) were obtained
from the University of Florida using an Agilent 6220 TOF, a Bruker
Daltonics, or an Impact II QTOF instrument.
d
146.5, 128.9 (2C), 123.7 (4C), 115.9 (2C), 49.38(2), 33.2, 32.4 (2C),
28.8 (4C). HR-MS (ESI): m/z Calcd. for [C23H27NO6þH]þ ¼ 414.1917,
Found 414.1948 (þ7.5 ppm). Spectral data for compound 13a were
consistent with the data previously reported in the literature [30].
4.1.1. 6,6-Dimethyl-9-(4-nitrophenyl)-5,6,7,9-tetrahydrofuro [3,4-
b]quinoline-1,8(3H,4H)-dione 12a
SMILES:O]C1C(C(C2¼CC]C([Nþ]([O])
¼
O)C]C2)([H])
C3¼C(O[H])CC(C)(C)CC3¼O)]C(O[H])CC(C)(C)C1.
4.1.3. 8-(4-nitrophenyl)-5,8-dihydro-1H,3H-difuro[3,4-b:30,40-e]
pyridine-1,7(4H)-dione 14a
In a flame dried 20 mL scintillation vial, under argon, dimedone
10 (70 mg, 0.50 mmol, 1.0 eq.), p-nitrobenzaldehyde 5a (76 mg,
0.50 mmol, 1.0 eq.), pyrrolidine (50 mL, 0.50 mmol, 1.0 eq.) and in-
dium chloride (13 mg, 0.050 mmol, 10 mol%) were dissolved in
acetonitrile (2.5 mL, 0.20 M). The reaction mixture was stirred at
room temperature for 2 h to obtain the intercepted-Knoevenagel
product 16 in situ. Tetronic acid 6 (60 mg, 0.60 mmol, 1.2 eq.) was
then added directly to the vial and the mixture was left stirred at
room temperature for 1.5 h. Acetonitrile was evaporated under
vacuum to obtain the crude yellow solid, and an extraction was
achieved with CH2Cl2 (3 ꢂ 20 mL) and water (5.0 mL). Note: Neutral
condition must be used to avoid the spontaneous cyclization of 12a
into 11a. The combined organic layers were dried over Na2SO4 and
evaporated under vacuum to obtain the crude dienol 12a as a light-
yellow solid (130 mg, 0.35 mmol, 70% crude yield, 2 steps). Rf ¼ 0.41
In a flame dried round bottom flask, a mixture of p-nitro-
benzaldehyde 5a (76 mg, 0.50 mmol, 1.0 eq.), tetronic acid 6
(100 mg, 1.0 mmol, 2.0 eq.) and ammonium acetate (39 mg,
0.50 mmol,1.0 eq.) in ethanol (2.5 mL, 0.20 M) were stirred for a day
at rt. After solvent evaporation under vacuum, product 14a was
recrystallized in hexane, filtered and dried (75 mg, 0.225 mmol,
45% yield). Rf¼0.49 (EtOAc/hexanes 30:70; UV Active; stains white
in KMnO4). IR
nmax (neat): 3340, 1727, 1514, 1455, 1371, 1326, 1210,
1019, 975, 848, 777, 738, 696 cmꢁ1
.
1H NMR (400 MHz, CD3OD):
d
(ppm) 9.65 (d, J ¼ 8.8 Hz, 2H), 9.15e9.06 (m, 2H), 6.36 (s, 1H), 6.03
(d, J ¼ 1.2 Hz, 5H). 13C NMR (100 MHz, CD3OD):
d (ppm) 183.9 (2C),
(EtOAc/MeOH 9:1). Mp ¼ 135 5 ꢀC. IR
n
max (neat): 3340, 1727,
180.5 (2C), 152.9, 147.5, 129.1 (2C), 124.4 (2C), 99.1 (2C), 70.0 (2C),
34.0. HRMS (ESI): m/z Calcd. for [C15H11NO8þH]þ ¼ 334.0563,
Found 334.0589 (þ7.8 ppm). Spectral data for compound 14a were
consistent with the data previously reported in the literature [31].
SMILES: [H]N1C2 ¼ C(C(OC2) ¼ O)C(C3¼CC]C([Nþ]([O-]) ¼ O)C]
C3)C4¼C1COC4 ¼ O.
1514, 1455, 1371, 1326, 1210, 1019, 975, 848, 777, 738, 696 cmꢁ1. 1H
NMR (400 MHz, CD3OD)
d
(ppm): 8.06 (d, J ¼ 8.9 Hz, 2H), 7.37 (d,
J ¼ 8.9 Hz, 2H), 5.70 (s, 1H), 4.57 (d, J ¼ 15.6 Hz, 1H), 4.46 (d,
J ¼ 15.6 Hz, 1H), 2.28 (s, 4H), 1.06 (s, 6H). 13C NMR (100 MHz,
CD3OD)
d (ppm): 191.3, 183.1, 180.2 (2C), 152.7, 147.2, 129.2 (2C),
124.0 (2C), 117.3, 99.3, 69.3, 46.7, 32.6, 32.5, 28.6 (2C), 25.0. HRMS
(ESI) m/z: [M-H20 þ H]þ Calcd for [C19H17NO6þH]þ 356.1129; Found
356.1126 (0.8 ppm).
4.2. General procedure A for the preparation of unsymmetrical 4H-
pyrans 11
SMILES: OC(CC(C)(C)C1) ¼ C(C(C2¼CC]C([Nþ]([O-]) ¼ O)C]
C2)C(C(OC3) ¼ O)]C3O)C1¼O.

C. Shearer et al. / Tetrahedron 75 (2019) 130606
7
32.9, 28.4 (2C). 13C NMR (100 MHz, CDCl3)
d
(ppm): 202.6, 178.5,
178.0 (2C), 147.3, 146.6,127.5 (2C), 123.8 (2C),115.4, 101.0, 68.0, 50.6,
43.4, 32.3, 31.6, 28.4 (2C). HRMS (ESI) m/z: [MþH]þ Calcd for
C19H18NO6 356.1129; Found 356.1128 (0.3 ppm). SMILES:
O¼C(OC1)C2¼C1OC3 ¼ C(C(CC(C)(C)C3) ¼ O)C2C4 ¼ CC]
C([Nþ]([O-]) ¼ O)C]C4.
4.2.2. 6,6-Dimethyl-9-(3-nitrophenyl)-5,6,7,9-tetrahydro-1H-furo
[3,4-b]chromene-1,8(3H)-dione 11c
In a flame dried 20 mL scintillation vial under argon, dimedone
or 1,3-cyclohexandione (0.50 mmol, 1.0 eq.), a selected benzalde-
hyde (0.50 mmol, 1.0 equiv.), pyrrolidine (50 mL, 0.50 mmol, 1.0 eq.)
and indium chloride (0.05 mmol, 10 mol%) were dissolved in
acetonitrile (2.5 mL, 0.20 M). The reaction mixture was stirred at
room temperature for the indicated amount of time (t1 in h). Note 1:
Intercepted intermediate 16 formed a precipitate in the reaction
media. A selected 1,3-dicarbonyl molecule (0.60 mmol, 1.2 eq.) was
then added directly to the vial and the mixture was stirred at room
temperature until reaction completion (t2 in h). Note 2: The inter-
cepted intermediate 16 disappeared over time after the addition of
the 1,3-dicarbonyl partner to the reaction media. A HCl solution
(10 mL, 0.50 M) was then poured into the reaction mixture, and
stirred for 15 min to achieve cyclization. Three distinct methods of
isolation have been developed. Procedure A1: If a precipitate formed
during stirring with HCl, the product can directly be filtered and
washed with cold ethyl acetate (2 X ~2.0 mL). Procedure A2: If no
precipitate appeared after stirring with HCl, an extraction was
achieved with CH2Cl2 (3 ꢂ 20 mL) and the combined organic layers
were dried over Na2SO4 and evaporated under vacuum. The crude
product was then purified by trituration with minimum amounts of
ethyl acetate (2 X ~2.0 mL). Procedure A3: If the crude product after
extraction/evaporation is an oil, the oil can be triturated with pe-
troleum ether and the resulting solid can then be filtered and
triturated a second time with ethyl acetate (2 X ~2.0 mL) to isolate
the desired product 11.
Compound 11c was synthesized from m-nitrobenzaldehyde
(76 mg, 0.50 mmol, 1.0 eq.) at room temperature, and purified
accordingly to general procedure A1 (t1 ¼ 2 h, t2 ¼ 2 h) to be obtained
in pure form as a white solid (128 mg, 0.36 mmol, 73% yield).
Rf ¼ 0.51 (EtOAc/MeOH 9:1). Mp ¼ 138 5 ꢀC. IR
nmax (Neat):
3335, 1798, 1505, 1399, 1368, 1308, 1210, 1025, 970, 849, 777, 738,
698 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d (ppm): 8.10e8.03 (m, 1H),
8.02e7.95 (m, 1H), 7.52e7.40 (m, 2H), 5.53 (s, 1H), 4.88 (d,
J ¼ 16.6 Hz, 1H), 4.70 (d, J ¼ 16.6 Hz, 1H), 2.73 (d, J ¼ 17.9 Hz, 1H),
2.64 (d, J ¼ 17.9 Hz, 1H), 2.34 (d, J ¼ 16.8 Hz, 1H), 2.27 (d, J ¼ 16.8 Hz,
1H), 1.19 (s, 3H), 1.09 (s, 3H). 13C NMR (100 MHz, CDCl3)
d (ppm):
202.5, 178.6, 177.9 (2C), 148.7, 141.6, 132.7, 129.5, 121.9, 121.7, 115.3,
101.2, 68.1, 50.7, 43.4, 32.3, 31.4, 28.7, 28.3. HRMS (ESI) m/z:
[M þ NH4]þ Calcd for C19H21N2O6 373.1394; Found 373.1385
(2.4 ppm).
SMILES:
O]C(OC1)C2¼C1OC3 ¼ C(C(CC(C)(C)C3) ¼ O)
C2C4 ¼ CC]CC([Nþ]([O-]) ¼ O)]C4.
4.2.1. 6,6-Dimethyl-9-(4-nitrophenyl)-5,6,7,9-tetrahydro-1H-furo
[3,4-b]chromene-1,8(3H)-dione 11a
4.2.3. 8-(4-Nitrophenyl)-5,8-dihydro-1H,3H-difuro[3,4-b:30,40-e]
pyridine-1,7(4H)-dione 11d
Compound 11a was synthesized from p-nitrobenzaldehyde
(76 mg, 0.50 mmol, 1.0 eq.) at room temperature and purified
accordingly to general procedure A2 (t1 ¼ 2 h, t2 ¼ 1.5 h) to obtain
11a in pure form as a white solid (156 mg, 0.43 mmol, 88% yield).
nmax (neat): 3340,
1727, 1514, 1455, 1371, 1326, 1210, 1019, 975, 848, 777, 738,
Compound 11d was synthesized from m-chlorobenzaldehyde
(71 mg, 0.50 mmol, 1 eq.) at room temperature, and purified
accordingly to general procedure A3 (t1 ¼ 2 h, t2 ¼ 2 h) to be obtained
in pure form as a white solid (129 mg, 0.37 mmol, 75% yield).
Rf ¼ 0.51 (EtOAc/MeOH 9:1). Mp ¼ 135 5 ꢀC. IR
Rf ¼ 0.53 (EtOAc/MeOH 9:1). Mp ¼ 126 5 ꢀC. IR
nmax (Neat):
696 cmꢁ1. 1H NMR (400 MHz, CD3OD)
d
(ppm): 8.10 (d, J ¼ 8.8 Hz,
2958, 1714, 1638, 1593, 1570, 1469, 1380, 1313, 1260, 1178, 1156,
2H), 7.37 (d, J ¼ 8.2 Hz, 2H), 5.59 (s, 1H), 4.73 (d, J ¼ 16.0 Hz, 1H),
1126, 1074, 1031, 999, 891, 790, 777, 709, 681 cmꢁ1.1H NMR
4.58 (d, J ¼ 16.0 Hz, 1H), 2.38 (s, 4H), 1.08 (s, 6H). 1H NMR (400 MHz,
(400 MHz, CDCl3)
d
(ppm): 7.22e7.14 (m, 2H), 7.08 (d, J ¼ 1.7 Hz,
DMSO‑d6)
d
(ppm): 8.09 (d, J ¼ 8.8 Hz, 2H), 7.33 (d, J ¼ 8.8 Hz, 2H),
1H), 7.02e6.98 (m, 1H), 5.43e5.39 (m, 1H), 4.83 (d, J ¼ 16.5 Hz, 1H),
4.67 (d, J ¼ 16.5 Hz, 1H), 2.66 (d, J ¼ 17.7 Hz, 1H), 2.58 (d, J ¼ 17.7 Hz,
1H), 2.33 (d, J ¼ 16.7 Hz, 1H), 2.25 (d, J ¼ 16.7 Hz, 1H), 1.16 (s, 3H),
5.35 (s, 1H), 4.74 (d, J ¼ 16.1 Hz, 1H), 4.64 (d, J ¼ 16.1 Hz, 1H), 2.35 (s,
4H), 1.01 (s, 6H). 1H NMR (400 MHz, CDCl3)
d
(ppm): 8.12 (d,
J ¼ 8.9 Hz, 2H), 7.28 (s, 2H), 5.52 (s,1H), 4.86 (d, J ¼ 16.6 Hz,1H), 4.70
(d, J ¼ 16.6 Hz, 1H), 2.71 (d, J ¼ 18.0 Hz, 1H), 2.63 (d, J ¼ 18.0 Hz, 1H),
2.33 (d, J ¼ 16.8 Hz, 1H), 2.26 (d, J ¼ 16.8 Hz, 1H), 1.16 (s, 3H), 1.08 (s,
1.08 (s, 3H). 13C NMR (100 MHz, CDCl3)
d (ppm): 202.5, 178.7, 177.8
(2C), 141.5, 134.5, 129.7, 126.9, 126.6, 124.8, 115.6, 101.3, 67.9, 50.7,
43.5, 32.2, 31.1, 28.4 (2C). HRMS (ESI) m/z: [MþH]þ Calcd for
3H). 13C NMR (100 MHz, CD3OD)
d
(ppm): 191.2, 178.1, 177.5 (2C),
C19H18ClO4 345.0888; Found 345.0873 (4.3 ppm).
150.1, 147.5, 130.4, 128.9 (2C), 124.2 (2C), 116.2, 101.1, 68.3, 47.8, 33.2,
SMILES:
O]C(OC1)C(C2C3 ¼ CC]CC(Cl)]

8
C. Shearer et al. / Tetrahedron 75 (2019) 130606
C3) ¼ C1OC4 ¼ C2C(CC(C)(C)C4) ¼ O.
4.2.6. 9-(2-chlorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-1H-furo
[3,4-b]chromene-1,8(3H)-dione 11g
4.2.4. 9-(2-Chlorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-1H-furo
[3,4-b]chromene-1,8(3H)-dione 11e
Compound 11g was synthesized from o-chlorobenzaldehyde
(70 mg, 0.50 mmol, 1.0 eq.) at room temperature, and purified
accordingly to general procedure A2 (t1 ¼ 2 h, t2 ¼ 2 h) to be obtained
in pure form as a white solid (145 mg, 0.46 mmol, 92% yield). Two
atropoisomers are observed by 1H NMR at room temperature in an
88:12 ratio [13]. Rf ¼ 0.52 (EtOAc/MeOH 9:1). Mp ¼ 138 5 ꢀC. IR
Compound 11e was synthesized from o-chlorobenzaldehyde
(70 mg, 0.50 mmol, 1.0 eq.) at room temperature and purified
accordingly to general procedure A2 (t1 ¼ 2 h, t2 ¼ 2 h) to be obtained
in pure form as a white solid (143 mg, 0.41 mmol, 83% yield). Two
atropoisomers are observed by 1H NMR at room temperature in an
n
max (Neat): 3141, 2947, 1714, 1633, 1555, 1442, 1415, 1385, 1305,
1253, 1200, 1158, 1118, 1005, 968, 914, 858, 758, 742 cmꢁ1. 1H NMR
(400 MHz, CDCl3)
88:12 ratio [13]. Rf ¼ 0.53 (EtOAc/MeOH 9:1). Mp ¼ 141 5 ꢀC. IR
n
max (Neat): 3059, 2958, 1721, 1667, 1591, 1469, 1418, 1379, 1316,
1281, 1259, 1202, 1169, 1109, 1037, 1016, 941, 908, 813, 754,
d
(ppm): 7.29 (dd, J ¼ 7.5, 1.6 Hz, 1H), 7.25 (dd,
J ¼ 7.5, 1.6 Hz, 1H), 7.17 (dtd, J ¼ 13.1, 7.3, 3.5 Hz, 2H), 5.29 (s, 1H),
727 cmꢁ1.1H NMR (400 MHz, DMSO‑d6)
d (ppm): 7.37 (dd,
4.67 (d, J ¼ 16.0 Hz, 1H), 4.58 (d, J ¼ 16.0 Hz, 1H), 2.39-2.36 (m, 4H),
1.90e1.76 (m, 2H). 13C NMR (100 MHz, DMSO‑d6)
d (ppm): 195.7,
J ¼ 7.6 Hz, 1.6 Hz, 1H), 7.30 (dd, J ¼ 7.6, 1.6 Hz, 1H), 7.21 (td, J ¼ 7.5,
1.7 Hz, 1H), 7.15 (td, J ¼ 7.5, 1.7 Hz, 1H), 5.49 (s, 1H), 4.76 (d,
J ¼ 16.3 Hz, 1H), 4.63 (d, J ¼ 16.3 Hz, 1H), 2.59 (s, 2H), 2.32 (d,
J ¼ 16.6 Hz, 1H), 2.24 (d, J ¼ 16.6 Hz, 1H), 1.10 (s, 3H), 1.06 (s, 3H). 13C
174.3 (2C), 172.9, 138.8, 132.6, 130.4, 129.1, 127.4, 126.1, 113.7, 99.6,
66.3, 33.1 (2C), 31.5, 20.3. HRMS (ESI) m/z: [MþH]þ Calcd for
C17H14ClO4 317.0575; Found 317.0574 (0.3 ppm).
NMR (100 MHz, DMSO‑d6)
d (ppm): 195.5, 174.1, 174.0, 172.8, 139.1,
SMILES:
O]C(OC1)C(C2C3 ¼ CC]CC]C3Cl)]
132.5,130.5,128.9,127.3,126.0,112.4, 99.4, 66.1, 46.6, 31.5, 31.4 (2C),
27.8 (2C). HRMS (ESI) m/z: [MþH]þ Calcd for C19H18ClO4 345.0888;
Found 345.0877 (3.2 ppm).
C1OC4 ¼ C2C(CC([H])([H])C4) ¼ O.
4.2.7. 9-(4-fluorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-1H-furo
[3,4-b]chromene-1,8(3H)-dione 11h
SMILES:
C1OC4 ¼ C2C(CC(C)(C)C4) ¼ O.
O]C(OC1)C(C2C3 ¼ CC]CC]C3Cl)]
4.2.5. 9-(2-chlorophenyl)-6,6-dimethyl-1-thioxo-1,3,5,6,7,9-
hexahydro-8H-furo [3,4-b]chromen-8-one 11f
Compound 11h was synthesized from p-fluorobenzaldehyde
(62 mg, 0.50 mmol, 1.0 eq.) at room temperature, and purified
accordingly to general procedure A3 (t1 ¼ 2 h, t2 ¼ 2.5 h) to be ob-
tained in pure form as a white solid (96 mg, 0.29 mmol, 58% yield).
Synthesis of the tetronic acid thiono-analogue was achieved in
three steps accordingly to a literature precedent [32]. Compound
11f was synthesized from o-chlorobenzaldehyde (70 mg,
0.50 mmol,1.0 eq.) at room temperature and purified accordingly to
general procedure A2 (t1 ¼ 2 h, t2 ¼ 1.5 h) to be obtained in pure form
as a white-yellow solid (170 mg, 0.47 mmol, 94% yield). Rf ¼ 0.50
Rf ¼ 0.56 (EtOAc/MeOH 9:1). Mp ¼ 136 5 ꢀC. IR
nmax (Neat):
2957, 2920, 2851, 1710, 1634, 1505, 1377, 1269, 1157, 1033, 927, 766,
715 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d
(ppm): 7.08 (d, J ¼ 5.3 Hz,
1H), 7.06 (d, J ¼ 5.3 Hz, 1H), 6.94 (t, J ¼ 8.6 Hz, 2H), 5.45 (s, 1H), 4.80
(d, J ¼ 16.4 Hz, 1H), 4.66 (d, J ¼ 16.5 Hz, 1H), 2.65 (d, J ¼ 17.8 Hz, 1H),
2.59 (d, J ¼ 17.4 Hz, 1H), 2.32 (d, J ¼ 16.6 Hz, 1H), 2.25 (d, J ¼ 16.7 Hz,
(EtOAc/MeOH 9:1). Mp ¼ 142 5 ꢀC. IR
nmax (Neat): 2958, 1619,
1522, 1469, 1409, 1385, 1326, 1325, 1298, 1156, 1124, 1075, 1027,
1014, 962, 886, 777, 749, 705 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
1H), 1.14 (s, 3H), 1.07 (s, 3H). 13C NMR (100 MHz, CDCl3)
d (ppm):
d
(ppm): 7.42 (dd, J ¼ 7.7, 1.7 Hz, 1H), 7.33 (dd, J ¼ 7.7, 1.7 Hz, 1H),
202.4, 178.8, 177.4, 177.2, 161.5 (d, J ¼ 244.8 Hz), 134.5, 128.2 (d,
J ¼ 7.8 Hz, 2C), 116.0, 115.4 (d, J ¼ 21.3 Hz, 2C). 102.0, 68.0, 60.6, 50.7,
43.4, 32.1, 30.9, 28.5. HRMS (ESI) m/z: [MþH]þ Calcd for C19H18FO4
329.1184; Found 329.1186 (0.6 ppm).
7.23 (td, J ¼ 7.6, 1.7 Hz, 1H), 7.19 (td, J ¼ 7.6, 1.7 Hz, 1H), 5.72 (s, 1H),
5.10 (d, J ¼ 18.5 Hz, 1H), 4.92 (d, J ¼ 18.5 Hz, 1H), 2.53-2.45 (m, 2H),
2.37e2.10 (m, 2H), 1.09 (s, 3H), 1.06 (s, 3H). 13C NMR (100 MHz,
CDCl3)
d
(ppm): 216.9, 190.1, 178.8, 135.6, 133.3, 130.3, 129.4, 128.3,
SMILES:
C2C4 ¼ CC]C(F)C]C4.
O]C(OC1)C2¼C1OC3 ¼ C(C(CC(C)(C)C3) ¼ O)
126.6, 117.2, 115.6, 115.2, 74.6, 35.2 (2C), 31.6 (2C), 28.5, 28.2. HRMS
(ESI) m/z: [M þ H20 þ H]þ Calcd for C19H20ClO4S 379.0761; Found
379.0770 (2.4 ppm).
4.2.8. 9-Phenyl-5,6,7,9-tetrahydro-1H-furo [3,4-b]chromene-
SMILES:
C1OC4 ¼ C2C(CC(C)(C)C4) ¼ O.
S]C(OC1)C(C2C3 ¼ CC]CC]C3Cl)]
1,8(3H)-dione 11i

C. Shearer et al. / Tetrahedron 75 (2019) 130606
9
Compound
11k
was
synthesized
from
p-thio-
methylbenzaldehyde (76 mg, 0.50 mmol, 1.0 eq.) at room temper-
ature, and purified accordingly to general procedure A2 (t1 ¼3 h,
t2 ¼ 2.5 h) to be obtained in pure form as a white solid (110 mg,
0.31 mmol,
62%
yield)
Rf ¼ 0.53
(EtOAc/MeOH
9:1).
Mp ¼ 141 5 ꢀC. IR
n
max (Neat): 2957, 1713, 1637, 1576, 1380, 1313,
1260, 1047, 969, 860, 727 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
(ppm)
7.16 (d, J ¼ 8.4 Hz, 2H), 7.09e7.00 (m, 2H), 5.42 (s, 1H), 4.80 (d,
J ¼ 16.4 Hz, 1H), 4.66 (d, J ¼ 16.4 Hz, 1H), 2.61-2.59 (m, 2H), 2.44 (s,
3H), 2.30-2.26 (m, 2H), 1.13 (s, 3H), 1.01 (s, 3H). 13C NMR (100 MHz,
Compound 11i was synthesized from benzaldehyde (53 mg,
0.50 mmol, 1.0 eq.) at room temperature, and purified accordingly
to general procedure A2 (t1 ¼ 2.5 h, t2 ¼ 2.5 h) to be obtained in pure
form as a white solid (130 mg, 0.46 mmol, 92% yield). Rf ¼ 0.52
CDCl3) d (ppm): 202.3,178.8,177.2 (2C),136.2,136.1,127.2 (2C),127.1
(2C), 116.0, 102.0, 68.0, 50.7, 43.4, 32.1 (2C), 31.0, 28.5, 16.2. HRMS
(ESI) m/z: [M þ H20 þ H]þ Calcd for C20H23O5S 375.1289; Found
375.1266 (6.1 ppm). SMILES: O]C(OC1)C2¼C1OC3 ¼ C(C(CC(C)(C)
C3) ¼ O)C2C4 ¼ CC]C(SC)C]C4.
(EtOAc/MeOH 9:1). Mp ¼ 138 5 ꢀC. IR
nmax (Neat): 2940, 1709,
1634, 1558, 1413, 1185, 1045, 1020, 981, 857, 793, 716, 693 cmꢁ1. 1H
NMR (400 MHz, CDCl3)
d
(ppm): 7.27 (t, J ¼ 7.4 Hz, 2H), 7.22e7.16
(m, 1H), 7.13 (d, J ¼ 8.2 Hz, 2H), 5.41 (s, 1H), 4.81 (d, J ¼ 16.4 Hz, 1H),
4.66 (d, J ¼ 16.6 Hz, 1H), 2.78 (d, J ¼ 17.6 Hz, 1H), 2.69 (d, J ¼ 17.4 Hz,
1H), 2.45 (d, J ¼ 17.8 Hz, 1H), 2.37 (d, J ¼ 14.1 Hz, 1H), 2.12e1.95 (m,
4.2.11. 6,6-Dimethyl-9-(3,4,5-trimethoxyphenyl)-5,6,7,9-
tetrahydro-1H-furo [3,4-b]chromene-1,8(3H)-dione 11l
2H). 13C NMR (100 MHz, CDCl3)
d (ppm): 202.5, 178.9, 178.7, 176.7,
138.3, 128.6 (2C), 126.5 (2C), 126.4, 117.5, 102.2, 68.1, 36.8, 31.6, 29.9,
20.2. HRMS (ESI) m/z: [M þ H20 þ H]þ Calcd for C17H17O5 301.1076;
Found
301.1226
(50 ppm).
SMILES:
O]C(OC1)
C2¼C1OC3 ¼ C(C(CC(C)(C)C3) ¼ O)C2C4 ¼ CC]CC]C4.
4.2.9. 9-(4-methoxyphenyl)-5,6,7,9-tetrahydro-1H-furo [3,4-b]
chromene-1,8(3H)-dione 11j
Compound
11l
was
synthesized
from
3,4,5-
methyloxybenzaldehyde (53 mg, 0.50 mmol, 1.0 eq.) at room tem-
perature, and purified accordingly to general procedure A1 (t1 ¼ 2 h,
t2 ¼ 2.5 h) to be obtained in pure form as a white solid (42 mg,
0.10 mmol,
21%
yield).
Rf ¼ 0.55
(EtOAc/MeOH
9:1).
Mp ¼ 130 5 ꢀC. IR
nmax (Neat): 2940, 1709, 1634, 1558, 1413, 1185,
1045, 1020, 981, 857, 793, 716, 693 cmꢁ1.1H NMR (400 MHz, CDCl3)
d
(ppm): 6.34 (d, J ¼ 1.1 Hz, 2H), 5.43e5.37 (m, 1H), 4.80 (d,
Compound 11j was synthesized from p-methyloxybenzaldehyde
(68 mg, 0.5 mmol, 1.0 eq.) at room temperature, and purified
accordingly to general procedure A2 (t1 ¼3 h, t2 ¼ 2.5 h) to be ob-
tained in pure form as a white solid (102 mg, 0.33 mmol, 65% yield).
J ¼ 16.6 Hz, 1H), 4.66 (d, J ¼ 16.5 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 6H),
2.62 (s, 2H), 2.36e2.24 (m, 2H), 1.17 (s, 3H), 1.10 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d (ppm): 202.1, 178.6, 177.3, 177.0, 153.2 (2C),
136.6, 134.6, 116.1, 104.1 (2C), 101.9, 67.8, 60.9, 56.2 (2C), 50.7, 43.4,
32.0, 31.5, 28.9, 27.9. HRMS (ESI) m/z: [MþH]þ Calcd for C22H25O7
401.1595; Found 401.1600 (1.2 ppm).
Rf ¼ 0.52 (EtOAc/MeOH 9:1). Mp ¼ 142 5 ꢀC. IR
nmax (Neat):
2947, 1719, 1642, 1507, 1374, 1244, 1172, 1022, 980, 823, 740 cmꢁ1.1H
NMR (400 MHz, DMSO‑d6)
d
(ppm): 6.95 (d, J ¼ 8.8 Hz, 2H), 6.78 (d,
SMILES:O]C(OC1)C2¼C1OC3 ¼ C(C(CC(C)(C)C3) ¼ O)
J ¼ 8.8 Hz, 2H), 5.29 (s, 1H), 4.76 (d, J ¼ 16.1 Hz, 1H), 4.61 (d,
C2C4 ¼ CC(OC)]C(OC)C(OC)]C4.
J ¼ 16.1 Hz, 1H), 3.69 (s, 3H), 2.50 (m, 4H), 1.88 (t, J ¼ 6.3 Hz, 2H). 13C
NMR (100 MHz, DMSO‑d6)
d (ppm): 175.8, 175.6, 157.7, 132.7, 127.8
4.2.12. 6,6-Dimethyl-9-(3,4,5-trimethoxyphenyl)-5,6,7,9-
(2C),116.7 (2C),113.9 (2C),101.0 (2C), 66.8, 55.4 (2C), 30.6 (2C), 20.5.
HRMS (ESI) m/z: [M þ H20 þ H]þ Calcd for C18H19O6 331.1221;
Found 331.1182 (12 ppm).
tetrahydro-1H-furo [3,4-b]chromene-1,8(3H)-dione 11m
SMILES:
C2C4 ¼ CC]C(OC)C]C4.
O]C(OC1)C2¼C1OC3 ¼ C(C(CC([H])([H])C3) ¼ O)
4.2.10. 6,6-Dimethyl-9-(4-(methylthio)phenyl)-5,6,7,9-tetrahydro-
1H-furo [3,4-b]chromene-1,8(3H)-dione 11k
Compound 11m was synthesized from 3,4,5-methylox-
ybenzaldehyde (98 mg, 0.50 mmol, 1.0 eq.) at room temperature
and purified accordingly to general procedure A1 (t1 ¼3 h, t2 ¼ 2.5 h)
to obtain in pure form as a white solid 11m (60 mg, 0.16 mmol, 32%
yield). Rf ¼ 0.55 (EtOAc/MeOH 9:1). Mp ¼ 132 5 ꢀC. IR
nmax
(Neat): 2950,1717,1641,1587,1505,1379,1280,1183,1121,1018, 977,

10
C. Shearer et al. / Tetrahedron 75 (2019) 130606
775, 725 cmꢁ1.1H NMR (400 MHz, CDCl3)
d
(ppm): 6.34 (t, J ¼ 1.2 Hz,
105 ꢀC. The reaction was then quenched with ice cold water
(1.0 mL). The resulting precipitate was filtered through a filter pa-
per, and the solid was triturate with ethanol (2 ꢂ 0.50 mL) to obtain
9a in pure form as a yellow solid (20 mg, 0.06 mmol, 50% overall
yield).
2H), 5.36 (s, 1H), 4.80 (d, J ¼ 16.6 Hz, 1H), 4.66 (dd, J ¼ 16.4, 1.9 Hz,
1H), 3.80 (s, 3H), 3.77 (s, 6H), 2.71 (s, 2H), 2.41 (s, 2H), 2.11e1.92 (m,
2H). 13C NMR (100 MHz, CDCl3)
d (ppm): 202.5, 178.7 (2C), 177.0,
153.2 (2C), 136.8, 134.4, 117.5, 104.1 (2C), 102.0, 67.9, 60.9, 56.2 (2C),
36.9, 31.7, 29.8, 20.3. HRMS (ESI) m/z: [MþH]þ Calcd for C20H21O7
373.1282; Found 373.1287 (1.3 ppm).
Compound 9a was also synthesized from compound 11a, using
the following procedure. In a flame dried 10 mL scintillation vial
under argon, 11a (64 mg, 0.18 mmol, 1.0 eq.) and ammonium ace-
tate (23 mg, 0.30 mmol, 2.5 eq.) were dissolved in acetic acid
(0.60 mL, 0.20 M) and the reaction mixture was stirred for 4 h at
105 ꢀC. The reaction was then quenched with ice cold water
(1.0 mL). The resulted precipitate was filtered through a filter paper
and the solid was triturate with ethanol (2 ꢂ 0.50 mL) to obtain 9a
in pure form (40 mg, 0.11 mmol, 63% yield). Rf ¼ 0.78 (EtOAc/MeOH
SMILES:
O]C(OC1)C2¼C1OC3 ¼ C(C(CC([H])([H])C3) ¼ O)
C2C4 ¼ CC(OC)]C(OC)C(OC)]C4.
4.2.13. 3-Hydroxy-2-((2-hydroxy-6-oxocyclohex-1-en-1-yl)(4-
nitrophenyl)methyl)-5,5-dimethylcyclohex-2-en-1-one 12b
9:1). Mp ¼ 165 5 ꢀC. IR
n
max (neat): 2960, 1729, 1678, 1504, 1346,
1193, 1047, 999, 762 cmꢁ1. 1H NMR (400 MHz, DMSO‑d6)
d
(ppm):
10.20 (s, 1H), 8.12 (d, J ¼ 8.7 Hz, 2H), 7.47 (d, J ¼ 8.8 Hz, 2H), 4.95 (d,
J ¼ 16.3 Hz, 1H), 4.88 (d, J ¼ 17.4 Hz, 1H), 4.78 (s, 1H), 2.47 (d,
J ¼ 3.5 Hz, 2H), 2.21 (d, J ¼ 16.2 Hz, 1H), 2.07 (d, J ¼ 16.1 Hz, 1H), 1.03
(s, 3H), 0.96 (s, 3H).$13C NMR (100 MHz, DMSO‑d6)
d (ppm):195.1,
171.7, 157.3, 153.2, 151.6, 146.4, 129.5 (2C), 123.7 (2C), 110.3, 101.9,
65.9, 50.7, 35.1, 32.6 (2C), 28.9, 27.4. HRMS (ESI) m/z: [MþH]þ Calcd
for C19H19N2O5 355.1288; Found 355.1303 (4.2 ppm); [M þ NH4]þ
Calcd for C19H22N3O5 372.1554; Found 372.1549 (1.3 ppm). SMILES:
Compound 12b was synthesized from p-nitrobenzaldehyde
(76 mg, 0.50 mmol, 1.0 eq.) at room temperature, and purified
accordingly to general procedure A (t1 ¼ 2 h, t2 ¼ 2.5 h). After drying
the crude solid, a column chromatography using (Ethyl acetate/
methanol 9:1) was necessary to obtain 12b in pure form as a white-
yellow solid (141 mg, 0.365 mmol, 73% yield).; Rf ¼ 0.53 (EtOAc/
O]C(OC1)C(C2C3 ¼ CC]C([Nþ]([O-])
¼
O)C]
C3) ¼ C1NC4 ¼ C2C(CC(C)(C)C4) ¼ O.
4.2.15. 3-Hydroxy-5,5-dimethyl-2-((4-nitrophenyl)(pyrrolidin-1-
yl)methyl)cyclohex-2-en-1-one 16
MeOH 9:1). Mp ¼ 137 5 ꢀC. IR
n
max (Neat): 2956, 1723, 1583,
1513, 1491, 1343, 1291, 1032, 851, 731 cmꢁ1
.
1H NMR (400 MHz,
CDCl3)
d
(ppm): 12.03 (s, 1H), 11.84 (s, 1H), 8.12 (d, J ¼ 8.9 Hz, 2H),
7.27e7.23 (m, 2H), 5.50 (s,1H), 2.72e2.34 (m, 8H), 2.06 (dd, J ¼ 10.2,
4.8 Hz, 2H), 1.24 (s, 3H), 1.12 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
(ppm): 192.3, 191.9, 191.5, 188.9, 146.6, 146.3, 127.68 (2C), 123.6
(2C), 116.2, 114.8, 46.9, 46.8, 33.7, 33.5, 32.8, 31.4, 29.9, 27.4, 20.2.
HRMS (ESI) m/z: [MþH]þ Calcd for C21H24NO6 386.1598; Found
386.1607 (2.3 ppm); [MþNa]þ Calcd for C21H23NO6Na 408.1418;
Found 408.1423 (1.2 ppm).
SMILES: OC(CC(C)(C)C1) ¼ C(C(C2¼CC]C([Nþ]([O-]) ¼ O)C]
C2)([H])C3¼C(O)CCCC3¼O)C1¼O.
Dimedone 10 (70 mg, 0.50 mmol, 1.0 eq.), p-nitrobenzaldehyde
5a (76 mg, 0.50 mmol, 1.0 eq.), and indium chloride (13 mg,
0.050 mmol, 10 mol%) were dissolved sequentially in anhydrous
4.2.14. 6,6-Dimethyl-9-(4-nitrophenyl)-5,6,7,9-tetrahydrofuro [3,4-
b]quinoline-1,8(3H,4H)-dione 9a
toluene (2.0 mL). Pyrrolidine (50 mL, 0.50 mmol, 1.0 eq.) was then
added and the reaction mixture was left to stir at room temperature
for 3 h. The reaction was then quenched with water (10 mL) and
extracted with dichloromethane (3 ꢂ 5.0 mL). The combined
organic layers were dried over Na2SO4 and dichloromethane was
evaporated to obtain the crude material as a yellow powder. The
yellow powder was then washed with diethyl ether to eliminate
residual traces of aldehyde and obtain 16 in a pure form (151 mg,
0.44 mmol, 88% yield). 1H NMR (400 MHz, CDCl3)
d 8.15 (d,
J ¼ 8.7 Hz, 2H), 7.73 (d, J ¼ 8.7 Hz, 2H), 5.07 (s, 1H), 3.54e3.37 (m,
1H), 2.89 (d, J ¼ 44.8 Hz, 2H), 2.39 (s, 1H), 2.20 (s, 4H), 2.00 (s, 5H),
0.97 (s, 6H). Spectral data for compound 16 are consistent with the
data previously reported in the literature [33].
In a flame dried 10 mL scintillation vial, under argon, dimedone
10 (17 mg, 0.12 mmol, 1.0 eq.), p-nitrobenzaldehyde 5a (18 mg,
0.12 mmol, 1.0 eq.), pyrrolidine (20
m
L, 0.12 mmol, 1.0 eq.) and in-
SMILES: O]C1CC(C)(C)CC(O)]C1C(C2¼CC]C([Nþ]([O-]) ¼ O)
dium chloride (2.0 mg, 0.01 mmol, 10 mol%) were dissolved in
acetonitrile (0.60 mL, 0.20 M). The reaction mixture was stirred at
room temperature for 2 h. Tetronic acid 6 (24 mg, 0.24 mmol, 1.2
eq.) was then added directly to the vial, and the mixture was stirred
at room temperature for 1.5 h. After full reaction conversion, as
confirmed by TLC, acetonitrile was evaporated to obtain the crude
product 12a which was dissolved in the same flask with acetic acid
(0.60 mL, 0.20 M). Ammonium acetate (23 mg, 0.30 mmol, 2.5 eq.)
was then added, and the solution and stirred under reflux for 4 h at
C]C2)([H])N3CCCC3.
Acknowledgments
We are very grateful for the financial support from the NIH
(NIGMS Grant: R15GM116025 to C.S. and S.S.S.). We would like also
to acknowledge the Florida Atlantic University Office of Under-
graduate Research and Inquiry for funding C.S. through several
Undergraduate Research Grants. The authors thank Ms. Margaret

C. Shearer et al. / Tetrahedron 75 (2019) 130606
(2009) 1754e1756;
11
Whims for obtaining some preliminary data on this project. The
authors also thank Dr. Kari B. Basso at the Mass Spectrometry
Research and Education Center from the Department of Chemistry
at the University of Florida for the high-resolution mass spec-
trometry analysis supported by the NIH (S10 OD021758-01A1).
(i) K.K. Pasunooti, C. Nixon Jensen, H. Chai, M.L. Leow, D.W. Zhang, X.W. Liu,
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Appendix A. Supplementary data
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