Chromene- And quinoline-3-carbaldehydes: Useful intermediates in the synthesis of heterocyclic scaffolds

Article abstract of DOI:10.3390/molecules25173791

Chromenes and quinolines are recognized as important scaffolds in medicinal chemistry. Herein, the efficient use of chromene- and quinoline-3-carbaldehydes to synthesize other valuable heterocycles is described. These carbaldehydes are obtained in excelle

Full text of DOI:10.3390/molecules25173791

molecules
Article
Chromene- and Quinoline-3-Carbaldehydes: Useful
Intermediates in the Synthesis of
Heterocyclic Scaffolds
Djenisa H. A. Rocha 1,2 , Vasco F. Batista 1, Emanuel J. F. Balsa 1 , Diana C. G. A. Pinto 1,
and Artur M. S. Silva 1
*
1
LAQV-REQUIMTE & Department of Chemistry, Campus de Santiago, University of Aveiro, 3810-193 Aveiro,
Portugal; djenisa@ua.pt (D.H.A.R.); vfb@ua.pt (V.F.B.); emanuelbalsa@ua.pt (E.J.F.B.);
artur.silva@ua.pt (A.M.S.S.)
CICECO-Aveiro Institute of Materials & Department of Chemistry, Campus de Santiago,
University of Aveiro, 3810-193 Aveiro, Portugal
2
*
Correspondence: diana@ua.pt
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Gianfranco Favi
Received: 27 July 2020; Accepted: 19 August 2020; Published: 20 August 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Chromenes and quinolines are recognized as important scaffolds in medicinal chemistry. Herein,
theefficientuseofchromene-andquinoline-3-carbaldehydestosynthesizeothervaluableheterocyclesisdescribed.
These carbaldehydes are obtained in excellent yields through the Vilsmeyer-Haack reaction of flavanones
and azaflavanones. Protocols towards the synthesis of new heterocycles, such as 3H-chromeno[3–c]quinolines,
(Z/E)-2-aryl-4-chloro-3-styryl-2H-chromenes, and (E)-2-aryl-4-chloro-3-styrylquinoline-1(2H)-carbaldehydes were
established. Altogether, we demonstrate the value of chromene- and quinoline-3-carbaldehydes as building blocks.
Keywords: chromene-3-carbaldehydes; 3-styryl-2H-chromenes; quinoline-3-carbaldehydes; 3H-chromeno
[3,4-c]quinolines; 3-styrylquinoline-1(2H)-carbaldehydes; Wittig reaction
1. Introduction
The synthesis of new heterocyclic compounds is a significant aspect of medicinal chemistry due
to the recognized value of this type of compound in the development of new drugs. In this regard,
quinoline and chromene cores are interesting frameworks owing to their established medicinal value.
Biological activities, such as anticancer [
and cardiovascular [ ], can be highlighted. These nuclei can be found in natural compounds [
and synthetic materials [13–15].
1
,
2
], antimicrobial [
3
–
5
], anti-Alzheimer’s [
6
], antioxidant [
7],
8
9–12]
In this manuscript, the usefulness of 4-chloro(chromene- and quinoline)-3-carbaldehydes in
the synthesis of other significant heterocycles is described. Moreover, the 4-chloro(chromene-
and quinoline)-3-carbaldehydes
Vilsmeyer-Haack reaction (Scheme 1) using flavanones
2
are easily obtained, in good to excellent yields, through a
(X = O) and 2-aryl-2,3-dihydroquinolines
1
1
(X = NH, azaflavanones), respectively. Recently we established a straightforward protocol to achieve,
in excellent yields, these flavanone and azaflavanone derivatives [16].
Among the significant heterocycles described are indole and quinoline derivatives recognized
bioactive alkaloids, for which-New synthetic methodologies are always essential to be established.
Moreover, the study of the use of 4-chloro(chromene- and quinoline)-3-carbaldehydes
2 in Wittig
reactions is also described and allowed the synthesis of interesting derivatives bearing a 3-styryl moiety.
The work herein reported, besides the diversity of structures obtained, also demonstrates the scope of
the transformations.
Molecules 2020, 25, 3791; doi:10.3390/molecules25173791
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Molecules 2020, 25, 3791
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5’
R
4’
R
6’
1
Y
C
4
Cl
(2)
B
8
8a
4a
3’
2
X
1’
7
6
2’
POCl3/DMF
A
3
CHO
5
R = H, OCH3, NO2
X = O, NH
Y = O, NCHO
O
(1)
Scheme 1. Synthesis of 4-chlorochromene-3-carbaldehydes 2a–c and 4-chloroquinoline-3-carbaldehydes 2d–f.
2. Results and Discussion
The Vilsmeyer-Haack formylation is an everyday procedure in our group [17,18] that was easily
used in the formylation of flavanones (Scheme 1, X = O) and, in the case of azaflavanones , (Scheme 1,
1
1
X = NH), required a few optimization steps. The quantities used and the reaction time were adjusted to
ensure the total formylation at botH-N-1 and C-3 and consequently avoid monoformylated derivatives.
Nuclear magnetic resonance experiments confirmed the structures of both 2-aryl-4-chloro-
2H-chromene-3-carbaldehydes 2a
The most typical features in their 1H-NMR spectra are the singlets at
corresponding to the resonance of H-2, respectively, for compounds 2a
signals are seen at = 10.27–10.32 and 10.30–10.33 ppm due to the formyl protons’ resonances.
In the 13C-NMR spectra, the signal due to the 3-CHO at
= 187.6–188.2 ppm and the signal due to
C-2 at = 73.8–75.0 ppm for compounds 2a and at = 50.2–50.6 ppm for compounds 2d should
be highlighted.
The indole nucleus is a prominent constituent of alkaloids such as serotonin and melatonin [19
also present in many bioactive alkaloids. Antitumoral [21 22], anti-arrhythmic [19], anti-inflammatory [23],
–c
and 2-aryl-4-chloro-1,2-dihydroquinoline-1,3-dicarbaldehydes 2d
= 6.33–6.47 and 6.88–7.00 ppm
and 2d . Other important
–f.
δ
–c
–f
δ
δ
δ
–c
δ
–f
,20] and is
,
antimicrobial [24], and antihypertensive properties are amongst the reported biological activities. The synthesis
of indole derivatives is largely explored due to relevant biological applications described for this scaffold,
and there are reports on the synthesis of indole hybrids [25
chromene-indole hybrids, so we studied the reaction of 2-aryl-4-chloro-2H-chromene-3-carbaldehydes 2a
with indole ( ). Unexpectedly, complex mixtures of compounds were obtained. The two major products’
isolation suggested that they were derivatives presenting one and two indole units, respectively.
–27]. We thought it would be interesting to obtain
–c
3
Furthermore, the 2-aryl-4-chloro-2H-chromene-3-carbaldehyde derivative was recovered as well
as some degradation products. The amount of DMSO used was optimized to a minimum, to allow
an excellent stirring. The best reaction temperature was established at 130 ◦C, to avoid the loss of
the formyl group. The amount of indole
3 added was established to prevent mixtures of hybrids
and maximize the yield of the two indole unit hybrid. This careful optimization of the reaction
conditions allowed us to obtain a single compound (Scheme 2) in very good yields (60 to 84%).
The MS spectrum of the obtained compound suggested that it should contain two indole units.
Furthermore, the NMR experiments confirmed this hypothesis and allowed us to establish that
the obtained compounds were 3,30-[(2-aryl-4-chloro-2H-chromen-3-yl)methylene]bis(1H-indoles) 4a
–c
as depicted in Scheme 2. We believe that the indole carbon C-3 nucleophilicity is high and that
the formyl carbon electrophilicity favors the reaction with a second indole unit. The main NMR
features are: (i) NH proton resonances at
(J 2 Hz) due to their coupling with H-2 in each indole unit; (ii) methinic proton of the carbon linked
to the two indole units, a singlet at δ = 6.14–6.25 ppm.
δ = 10.32–10.61 and 11.06–11.16 ppm, appearing as doublets
≈

Molecules 2020, 25, 3791
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R
R
H
N
O
O
DMSO
NH
+
130 oC, 24 h
CHO
(3)
Cl
Cl
(2)
HN
R = H, OCH3, NO2
(4)
Scheme 2. Synthesis of 3,30-[(2-aryl-4-chloro-2H-chromen-3-yl)methylene]bis(1H-indoles) 4a–c.
Next, the reactivity of 2-aryl-4-chloro-2H-chromene-3-carbaldehydes 2a–c with anilines 5 was
studied. The main objective was to obtain quinoline derivatives by forming an imine intermediate,
followed by its cyclization with the elimination of hydrochloric acid (Scheme 3).
3’
R
R
R
4’
5’
2’
1’
NH2
4
1
O
O
O
4a
6
3
2
r.t.
TFA, r.t.
72 h
6’
+
6a
12c
R2
1.5 h - 2.5 h
7
CHO
12b
12a
R1
Cl
N
R2
R1
N
Cl
(2)
12
8a
(5)
9
11
(6)
R1
10
R2
(7)
6b) R = H, R1 = R2 = OCH3; 17%
6f) R = NO2, R1 = R2 = OCH3; 9%
7a) R = R1 = R2 = H; 40%
7b) R = H, R1 = R2 = OCH3; 63%
7c) R = R1 = H, R2 = NO2; 25%
7d) R = OCH3, R1 = R2 = H; 50%
7e) R = OCH3, R1 = R2 = OCH3; 75%
7f) R = NO2, R1 = R2 = OCH3; 73%
Scheme 3. Synthesis of 6-aryl-6H-chromeno[3,4-c]quinolines 7a–f.
The first attempts, reacting 4-chloro-2-phenyl-2H-chromene-3-carbaldehyde 2a with aniline, gave
a mixture of products and indications that the imine derivative was either not stable, or not able to
resist the purification steps. Therefore, we decided to control the reaction by TLC, adding TFA to
promote the in situ cyclization immediately after the consumption of the 2a. This procedure proved
efficient and allowed the synthesis of the desired 6-phenyl-6H-chromeno[3,4-c]quinoline 7a in moderate
yield. Naturally, the reaction scope was further evaluated (Scheme 3). Although the reaction occurs
with certain success, we notice that the first step requires variable reaction times (from 1.5 to 2.5 h),
whereas the second step was accomplished in an additional 72 h. Other relevant results include
the lower or nonexistent reactivity of derivatives having nitro groups as substituents; only two novel
compounds, 7c and 7f, were obtained, the former in low yield (25%). On the other hand, the presence
of activating groups in the chromene-3-carbaldehydes, such as OCH3, improve the yield, cases of 7d
(50%), and 7e (75%). That is more evident when two methoxy substituents are present in aniline, which
increased reactivity, and all derivatives were obtained in very good yields (7b, 63%; 7e, 75%, 7f, 73%).
We were also able to isolate two imine derivatives (Scheme 3) in low yields, and 6f was obtained only
when the second step was shortened 48 h.
The main features in the NMR characterization of 6-aryl-6H-chromeno[3,4-c]quinolines 7a
the two singlets at = 6.32–6.44 and 7.30–7.60 ppm due to, respectively, H-6 and H-7 resonances.
Another typical signal is the double doublet appearing at = 8.40–8.55 ppm and corresponding to
–f are
δ
δ
the H-1 resonance. These signals were not only in agreement with the proposed structure (Scheme 3)
but also showed essential connectivities in the HMBC spectra that allowed the full characterization of
the synthesized 6-aryl-6H-chromeno[3,4-c]quinolines 7a–f.

Molecules 2020, 25, 3791
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3-Styrylchromenes constitute a small group of synthetic compounds recently reported for their
antiviral [ ], cytotoxic [28], and antimicrotubular activity [29]. Several methods for the synthesis of
the 3-styryl-2H-chromene nucleus have been described, including the Horner-Wadsworth-Emmons [
and Wittig [29] reactions. Considering this, we decided to assess the reactivity of 2-aryl-4-chloro-
2H-chromene-3-carbaldehydes 2a in a Wittig reaction with aromatic ylides (Scheme 4). Our first
3
3]
–c
9
approach was to use a previously established procedure [30], although with some adaptations, mainly
in the reaction times and the amount of base. The two isomers were always obtained, with a clear
preference for (Z)-2-aryl-4-chloro-3-styryl-2H-chromenes 11a
–
f
(Table 1, Scheme 4), as predicted by
Wittig reaction selectivity [31].
PPh3X
R1 = H, X = Cl
R1 = NO2, X = Br
R1 = OEt, X = Br
R1
(8)
dry THF
NaH
3’
R
R
4’
R
2’
PPh3
8
5’
8a
4a
O
O
2
O
R1
7
6
1’
dry THF
6’
β
+
2’’
+
3
1’’
3’’
CHO
4
α
5
4’’R1
5’’
Cl
Cl
Cl
(2)
R1
(9)
6’’
(10)
(11)
10/11a) R = R1 = H
10/11f) R = OCH3, R1 = NO2
10/11g) R = NO2, R1 = H
10/11h) R = NO2, R1 = OCH2CH3
10/11i) R = NO2, R1 = NO2
10/11b) R = H, R1 = OCH2CH3
10/11c) R = H, R1 = NO2
10/11d) R = OCH3, R1 = H
10/11e) R = OCH3, R1 = OCH2CH3
Scheme 4. Synthesis of (Z- and E)-2-aryl-4-chloro-3-styryl-2H-chromenes 10a–i and 11a–i.
The optimization steps demonstrated that the Wittig reaction results are dependent on both
the aldehyde
2 and the ylide 9. It is clear that the ylide 9c, having an electron-donating group,
requires less time to be formed, depends on the amount of base used and, in our opinion, also on
the solvent dryness; freshly distilled THF holds better results (Table 1). The aldehyde 2a was less
reactive. It requires longer reaction times, and the major isomer is obtained in lower yields (Table 1).
Another interesting result is that aldehyde 2c presents better results if the second step is performed at
room temperature (Table 1); in fact, reflux promotes aldehyde decomposition instead of improving
its reactivity.
The most important features of the 1H-NMR spectra of 2-aryl-4-chloro-3-styryl-2H-chromenes
10a
absolute configuration. In the (Z)-isomer 10a
frequency values than those of H- (6.22–6.63 ppm), and the stereochemistry of the vinylic system
was established as (Z) due to typical coupling constant values (3JH-α-H-β 12.1–12.3 Hz). In contrast,
in the (E)-isomer 11a , is the resonance of H- (7.42–7.75 ppm) that appears at higher frequency
–i
and 11a
–
i
are the signals of the vinylic protons, which allowed the establishment of the system
–i
, the resonance of H- (6.56-6.74 ppm) appears at higher
β
α
–
i
α
values, due to the chlorine atom’s proximity, than those of H-β (6.42–6.50 ppm). The vinylic system’s
stereochemistry was established as (E) due to typical coupling constant values (3JH-α-H-β 16.5–16.6 Hz)
and confirmed by the NOESY experiments.

Molecules 2020, 25, 3791
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Table 1. Optimization of reaction conditions for the synthesis of (Z and E)-2-aryl-4-chloro-3-styryl-2H-
chromenes 10a–f and 11a–i.
NaH a
(Equiv)
2nd Step c
(Time)
1st Step b
(Time)
(Z)-isomer d (E)-isomer d
Entry
Comp. 2
Ylide
9a
(Yield, %)
(Yield, %)
1
2
3
4
5
7
7
7
3 h
3 h
1.5 h
20 min
3 h
3 h 30 min
21 h
10a, 18
10a, 25
10a, 32
10a, 32
11a, 10
11a, 19
11a, 5
2a (R=H)
24 h
11a, 25
5
6
9b
9c
7
7
10 min
3 min
3 h 45 min
24 h
10b, 45
10c, 41
11b, 25
11c, 33
7
8
9
9a
9b
9c
7
8
8
15 min
5 min
3 min
3 h 50 min
3 h 30 min
3 h
10d, 50
10e, 50
10f, 53
11d, 28
11e, 20
11f, 35
2b (R=OCH3)
2c (R=NO2)
10
11
12
13
8
8
9
3
15 min
15 min
10 min
10 min
5 h
3 h
10g, -
10g, -
10g, 27
10g, 34
11g, -
11g, -
11g, -
9a
24 h f
40 min f
11g, 15
14
15
7
7
2 min
3 min
4 h
10h, 20
10h, 45
11h, -
11h, 24
9b
9c
1 h f
16
17
8
3
6 min
4 h
10i, -
10i, 52
11i, -
11i, 27
10 min e
2 hf
a Molar excess; b Time to obtain the ylide; c Time after the aldehyde addition; d Isolated compound yield in %; e THF
freshly dried; f Second step at room temperature.
The success achieved in the synthesis of 2-aryl-4-chloro-3-styryl-2H-chromene derivatives
prompt us to use the 2-aryl-4-chloro-1,2-dihydroquinoline-1,3-dicarbaldehydes 2d–f, aiming to
obtain new (Z- and E)-2-aryl-4-chloro-3-styrylquinolines. Therefore, we considered a previously
established procedure for the synthesis of 3-styryl-4-quinolones [32], using the reaction of
2-aryl-4-chloro-1,2-dihydroquinoline-1,3-dicarbaldehydes 2d
the phosphonium salts 8a (Scheme 5). A color change and TLC analysis controlled the formation
of ylide, being the ideal time for the ylides formation 15 min, 3 min, and 7 min, respectively, for 9a
9b, and 9c. After the ylide formation, aldehydes 2d were added to the reaction mixture. The first
–f with ylides 9a–c formed in situ from
–
c
,
–
f
results were not as good as expected (Table 2; Entries 1, 8, and 15). As so, the reaction conditions were
individually studied (Table 2). The analysis of Table 2 shows that the results depend on the aldehyde’s
reactivity and that the second step’s reaction time is a crucial parameter for the transformation.
PPh3X
R1 = H, X = Cl
R1 = NO2, X = Br
R1 = OEt, X = Br
12a) R = R1 = H
12c) R = H, R1 = NO2
R1
(8)
12d) R = OCH3, R1 = H
12e) R = OCH3, R1 = OCH2CH3
12f) R = OCH3, R1 = NO2
dry THF
NaH
12g) R = NO2, R1 = H
12h) R = NO2, R1 = OCH2CH3
3’
R
R
O
O
R
O
4’
5’
2’
PPh3
8
N
N
8a
N
2
R1
7
6
dry THF
1’
6’
β
+
2’’
+
3
1’’
3’’
4’’
4a
CHO
α
4
5
Cl
Cl
(2)
R1
(9)
6’’
Cl
R1
5’’
(12)
(13)
Scheme 5. Synthesis of (Z- and E)-2-aryl-4-chloro-3-styrylquinoline-1(2H)-carbaldehydes 12a–i and 13a–i.

Molecules 2020, 25, 3791
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Table 2. Optimization of reaction conditions for the synthesis of (E)-2-aryl-4-chloro-3-styrylquinoline-
1(2H)-carbaldehydes 12a–i.
2nd step a
(Time)
(E)-Isomer b
(Yield, %)
Entry
Comp. 2
Ylide
9a
Comp. 12
1
2
3
50 min
1 h 20 min
2 h
12a
12a
12a
35
40
44
2d (R=H)
4
5
46 min
1 h 30 min
12b
12b
17 c
35 c
9b
9c
6
7
2 h
3 h
12c
12c
33
40
8
9
10
45 min
1 h 20 min
2 h 20 min
12d
12d
12d
46
35
20
9a
2e (R=OCH3)
11
12
40 min
1 h 20 min
12e
12e
27
25
9b
9c
13
14
2 h
3 h
12f
12f
43
53
15
16
58 min
2 h 20 min
12g
12g
18
30
9a
9b
9c
17
2f (R=NO2)
45 min
12h
24
18
19
a
55 min
2 h
12i
12i
-
27c
Time after the aldehyde addition; b Isolated compound yield in %; c Mixture of the two isomers.
Another significant observation is that in this reaction, the (E)-isomer was the major product.
In contrast, the (Z)-isomer was obtained in vestigial amounts or just detected as an impurity in
1
the H-NMR spectra. For this reason, none of the (Z)-isomers were obtained as pure compounds.
In a few cases (Table 2; Entries 4, 5, 18, and 19), we could not isolate the (E)-isomer, because they are
light-sensitive, especially when in solution or silica gel. In other cases, increasing the second step
reaction time allowed the yield improvement (Table 2; Entries 3, 7, 14, and 16).
The ylide’s reactivity seems to influence the result, with the ylide 9c (R1=NO2) as the less reactive,
probably due to the electron-withdrawing group. Although 9b (R1=OCH2CH3) appeared to be more
reactive, with shorter reaction times in a few examples (Table 2; Entries 11 and 17), the yields were not as good
as expected. In terms of the aldehyde’s reactivity, 2-aryl-4-chloro-1,2-dihydroquinoline-1,3-dicarbaldehyde
2e is the most reactive. We were able to obtain all (E)-isomers, some in moderate yields (Table 2; Entries 8
and 14). Three crucial conclusions can be reached from these results:
(i) 2-Aryl-4-chloro-1,2-dihydroquinoline-1,3-dicarbaldehydes 2d–f are not as reactive as
the 2-aryl-4-chloro-3-styryl-2H-chromenes 2a–c;
(ii) The common Wittig reaction stereoselectivity was not observed, the (E)-isomer was obtained;
(iii) The formyl group at C-1 did not undergo Wittig reaction, naturally because of the amide carbonyl
group’s lower nucleophilicity.
The main features in the 1H-NMR spectra of (E)-2-aryl-4-chloro-3-styrylquinoline-1(2H)-carbaldehydes
12a–i
are the resonances of H-
α
and H-β, which appear as two doublets at
δ = 7.40–7.74 and 6.69–6.81 ppm,
respectively, and have coupling constants (J
group conformation (Scheme 5) was confirmed by NOESY experiments in whicH-NOE correlations between
H-β and H-2, H-20 were observed.
≈
16 Hz) typical of an (E)-configuration. The depicted 3-styryl
A DFT analysis on the reaction of benzyl triphenylphosphonium ylide with 2a was performed to
rationalize the abnormal selectivity obtained with the used complex aldehydes, considering the possible

Molecules 2020, 25, 3791
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formation of both (E and Z)-isomers. Previous reports have shown that the Wittig reaction mechanism
witH-Non-stabilized and semi-stabilized ylides proceeds through an early four-centre transition state
leading to the irreversible formation of a phosphoxetane intermediate; evidence clearly discards
the alternative existence of a betaine species. The reaction then passes through a secondary transition
state as the phosphoxetane degenerates to the desired alkene product. It has been established in
the literature that this first transition state’s nature determines the stereochemistry of the reaction,
locking the relative position of the aldehyde and ylide irreversibly [31].
Preliminary studies using the low level of theory B3LYP/STO-3G* to investigate the Wittig reaction
mechanism for these substrates were performed. Indeed, we verified the existence of a first high-energy
transition state (TS1), leading to planar OPA intermediates (Scheme 6). Significant puckering was
observed in TS1 for the (Z)-isomer, reducing unfavourable interactions between the aldehyde and ylide
substituents. The latter formation of the alkene undergoes a second transition state (TS2) with the P-C
bond’s advanced cleavage. Here too, some puckering is observed. Most importantly, this secondary
transition state was much lower in energy than TS1, supporting our hypothesis that selectivity is
controlled by relative configuration at TS1 and that the reaction is irreversible after this point.
Reagents
Products
CHO
N
CHO
N
Ph
+
+
O=PPh3
Ph3P
H
Cl
Cl
O
TS1
OPA
TS2
H
H
H
H
H
C
C
C
C
C
C
O
Ph3P
H
C
Ph3P
H
Ph3P
Ph3P
H
H
H
H
Ph3P
Ph3P
C
C
C
C
C
O
O
O
O
O
H
Z
E
Z
E
Z
E
Scheme 6. Preliminary investigation into the mechanism of the Wittig reaction.
Graph 1 shows the calculated potential energy profile for the reaction in study, here using a more
precise 6-31G(d) basis set. A similar high-energy transition state preceding phosphoxetane formation
was found for both configurations. The transition state TS1, shown in Scheme 6, has a geometry
consistent with previous works, with advanced formation of the C-C bond (1.94–2.14
Â) but mainly
electrostatic P-O interaction over 3 . The energy barrier of this rate-determining step of over 10 kcal/mol
Â
is higher than expected. This is most likely due to the complexity of the aldehyde structure, increasing
steric constraints in the transition state, and the charge distribution to the conjugated heterocyclic ring.
Comparing both isomers (Figure 1), significantly lower energy was found for the TS leading
to the (E)-isomer, in clear contradiction with most experimental and computational studies on
semi-stabilized ylides but in agreement with our experimental results. This suggests that additional
factors may play a role. In both cases, the transition state has an early character (C-C bond ~2.1
reduces steric interactions between substituents.
Â) that
Furthermore, the non-aromatiC-Nature of the aldehyde substituent allows increased flexibility to
reduce any steric constraints. However, the presence of the large aryl substituent on the C-2 sp3 carbon
limits its ability to assume a puckered state (described as an increase in the PCCO dihedral angle) as it
approaches the phosphine phenyl substituents. This is particularly relevant in the (Z)-isomer, where
puckering acts as a tool to reduce unfavorable interactions between the aldehyde and both the phosphine
and ylide substituents and thus reduce the energy of the transition state. Therefore, the restricted
puckering of the (Z)-TS1 may explain its higher energy in our calculations and the preference for
the formation of the E quinoline product.

Molecules 2020, 25, 3791
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Figure 1. Calculated potential energy surface for the reaction of 2a with triphenylphosphonium ylide 9a
.
3. Materials and Methods
3.1. General Experimental Procedures
Melting points were determined on a B-545 melting point apparatus (Büchi, Porto, Portugal)
1
and are uncorrected. H and 13C-NMR spectra were recorded on Avance III 300, Avance III HD 500,
and Avance III HD 700 [300.13 MHz (1H), 75.47 MHz (13C); 500.13 MHz (1H), 125.76 MHz (13C);
700.13 MHz (1H), 176,05 MHz (13C)] spectrometers (Bruker, Wissembourg, France) with TMS as
internal reference and with CDCl3 or DMSOd6 as solvent. Chemical shifts (δ) are reported in parts per
million values and coupling constants (J) in Hertz. Unequivocal 1H assignments were made using 2D
NOESY experiments (mixing time of 800 ms), while 13C assignments were made based on 2D gHSQC
(1H/13C) and gHMBC (delays for one bond and long-range JC/H couplings were optimized for 145
and 7 Hz, respectively) experiments. Positive-ion ESI mass spectra were acquired using a Q-TOF2
instrument (Bruker, Wissembourg, France). Nitrogen was used as nebulizer gas and argon as collision
gas. The needle voltage was set at 3000 V, with the ion source at 80 ◦C and desolvation temperature at
150 ◦C. Cone voltage was 35 V. High resolution mass spectra (HRMS-ESI+) were measure in a microTOF
(focus) mass spectrometer. Ions were generated using an Apollo ll (ESI) source (Bruker, Wissembourg,
France). Ionization was achieved by electrospray, using a voltage of 4500 V applied to the needle and a
counter voltage between 100 and 150 V applied to the capillary. Elemental analyses were obtained
with a 932 CHNS analyser (LECO, Madrid, Spain). Preparative thin layer chromatography was carried
out with Silica gel 60 GF254 (Merck KGaA, Porto, Portugal) and column chromatography using Silica
gel 0.060–0.020 mm 60A (Acros Organics, Porto, Portugal). All other chemicals and solvents were
obtained from commercial sources and used as received or dried using standard procedures.
3.2. General Procedure for the Vilsmeyer-Haack Formylation of Flavanones 1a–c and 2-aryl-2,3-
dihydroquinolin-4(1H)-one 1d–f
A mixture of POCl3 (0.1 mL, 1 mmol) in dry DMF (2 mL) was stirred under 0 ◦C during 15 min.
After that period, a solution of the appropriate 2-aryl-2,3-dihydroquinolin-4(1H)one 1d
in 10 mL CH2Cl2) or the appropriate flavanone 1a (21 mg, 0.1 mmol) was added and the reaction
was stirred at ~60 ◦C for 1.5 h to 2 h (in the case of 2-aryl-2,3-dihydroquinolin-4(1H)one 1d
) or 10
to 12 h (flavanone 1a ), depending on the starting material consumption. Then it was poured into
–f (0.1 mmol
–
c
–
f
–
c
a mixture of ice/water (10 g/15 mL) and the pH value was adjusted to 5 using a saturated solution
of NaHCO3. The solid obtained was filtered, dissolved in dichloromethane (25 mL) and the organic
phase was washed with water (3
sulfate and evaporated. The residue was purified by preparative thin layer chromatography using
×
25 mL). The organic phase was dried over anhydrous sodium
appropriate mixtures of eluent, CH2Cl2/hexane.
4-Chloro-2-phenyl-2H-chromene-3-carbaldehyde (2a). Yellow solid, yield (
1H-NMR (300.13 MHz, CDCl3):
6.40 (s, 1H, H-2); 6.89 (dd, 1H, H-8, J 1.3 and 8.1 Hz); 7.03 (ddd, 1H,
H-6, J 1.3, 7.1 and 8.1 Hz); 7.25-7.31 (m, 5H, H-20,30,40,50,60); 7.35 (ddd, 1H, H-7, J 1.3, 7.1 and 8.1 Hz);
η
) 95%, m. p. 101–103 ◦C.
δ

Molecules 2020, 25, 3791
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7.72 (dd, 1H, H-5, J 1.3 and 8.1 Hz); 10.30 (s, 1H, 3-CHO) ppm. 13C-NMR (75.47 MHz; CDCl3):
δ 75.0
(C-2); 117.4 (C-8); 120.0 (C-4a); 122.0 (C-6); 126.6 (C-5); 126.8 (C-20,60); 128.5 (C-30,50); 128.8 (C-40); 134.5
(C-7); 138.1 (C-10), 143.9 (C-4); 155.1 (C-8a); 188.2 (3-CHO) ppm. ESI+-MS m/z (%): 271.1 35Cl [M + H]+
(36); 273.1 37Cl [M + H]+ (24); 293.1 35Cl [M + Na]+ (70); 295.1 37Cl [M + Na]+ (6). EI-HRMS: calcd for
(C16H11O235Cl) 270.0448; found 270.0441. Calcd for (C16H11O237Cl) 272.0418; found 272.0409.
4-◦Chloro-2-(4-methoxyphenyl)-2H-chromene-3-carbaldehyde (2b). Yellow solid,
η 77%, m. p.
1
78–80 C. H-NMR (300.13 MHz, CDCl3):
δ
3.74 (s, 3H, 40-OCH3); 6.33 (s,1H, H-2); 6.79 (d large,
2H, H-30,50, J 9.2 Hz); 6,85 (dd, 1H, H-8, J 1.3 and 8.0 Hz); 7.02 (ddd, 1H, H-6, J 1.3, 7.1 and 8.0 Hz);
7.22 (dlarge, 2H, H-20,60, J 9.2 Hz); 7.33 (ddd, 1H, H-7, J 1.3, 7.1 and 8.0 Hz); 7.73 (dd, 1H, H-5, J 1.3
and 8.0 Hz); 10.27 (s, 1H, 3-CHO) ppm. 13C-NMR (75.47 MHz; CDCl3):
δ
55.2 (40-OCH3); 74.9 (C-2);
113.9 (C-30,50); 117.5 (C-8); 120.0 (C-4a); 121.9 (C-6); 126.4 (C-5); 126.9 (C-3); 128.3 (C-20,60); 130.1 (C-10);
134.4 (C-7); 143.6 (C-40); 143.9 (C-4); 155.0 (C-8a); 188.1 (3-CHO) ppm. ESI+-MS m/z (%): 301.1 35Cl [M +
H]+ (5); 303.1 37Cl [M + H]+ (100); 323.1 35Cl [M + Na]+ (40); 325.1 37Cl [M + Na]+ (2). EI+-HRMS: calcd
for (C17H13O335Cl) 300.0553, found 300.0563. Calcd. for (C17H13O337Cl) 302.0524, found 302.0527.
4-Chloro-2-(4-nitrophenyl)-2H-chromene-3-carbaldehyde (2c). Yellow solid, η
66%, m. p. 187–188 ◦C.
1H-NMR (300.13 MHz, CDCl3):
δ 6.47 (s, 1H, H-2); 6.97 (dd, 1H, H-8, J 1.3 and 8.1 Hz); 7.08 (ddd, 1H,
H-6, J 1.3, 7.1 and 8.1 Hz); 7.42 (ddd, 1H, H-7, J 1.3, 7.1 and 8.1 Hz); 7.47 (dlargo, 2H, H-20,60, J 9.0 Hz);
7.74 (dd, 1H, H-5, J 1.3 and 8.1 Hz); 8.13 (dlargo, 2H, H-30,50, J 9.0 Hz); 10.32 (s, 1H, 3-CHO) ppm. 13C-NMR
(75.47 MHz; CDCl3):
δ
73.8 (C-2); 117.4 (C-8); 119.0 (C-4a); 122.7 (C-6); 123.8 (C-30,50); 126.0 (C-3); 126.9 (C-5);
127.6 (C-20,60), 135.1 (C-7); 144.5 (C-4); 145.6 (C-10); 147.2 (C-40); 154.6 (C-8a); 188.1 (3-CHO) ppm. ESI+-MS
m/z (%): 316.1 35Cl [M + H]+ (100); 318.1 37Cl [M + H]+ (40); 338.1 35Cl [M + Na]+ (29); 340.1 37Cl [M + Na]+
(3). EI+-HRMS: calcd for (C16H10NO435Cl) 315.0298, found 315.0304. Calcd for (C16H10NO437Cl) 317.0269,
found 317.0278.
1
4-Chloro-2-phenyl-1,2-dihydroquinoline-1,3-dicarbaldehyde (2d). Yellow oil,
(300.13 MHz; CDCl3):
7.49 (t, 1H, H-7, J 7.6 Hz); 8.00 (d, 1H, H-5, J 7.8 Hz); 8.70 (s, 1H, NCHO); 10.32 (s, 1H, 3-CHO) ppm.
η
60%. H-NMR
δ
6.94 (s, 1H, H-2); 7.09-7.20 (m, 6H, H-20,30,40,50,60,8); 7.36 (t, 1H, H-6, J 7.6 Hz);
13C-NMR (75.47 MHz; CDCl3):
δ
50.6 (C-2); 118.4 (C-8); 126.0 (C-6); 127.1 (C-30,40); 127.7 (C-5); 128.5
(C-40); 128.7 (C-20,60); 131.0 (C-3); 133.2 (C-10); 133.4 (C-7); 136.8 (C-4a); 137.2 (C-8a); 142.9 (C-4); 160.6
(1-NCHO); 187.8 (3-CHO) ppm. MS (ESI+) m/z (%): 320.0 35Cl [M + Na]+ (100); 322.0 37Cl [M + Na]+ (3).
4-Chloro-2-(4-methoxyphenyl)-1,2-dihydroquinoline-1,3-dicarbaldehyde (2e). Yellow oil,
η 70%.
1H-NMR (300.13 MHz; CDCl3):
δ
3.71(s, 3H, 40-OCH3); 6.72 (d, 2H, H-30,50, J 8.6 Hz); 6.88 (s, 1H, H-2);
7.12 (d, 2H, H-20,60, J 8.6 Hz); 7.11-7.15 (m, 1H, H-8); 7.36 (t, 1H, H-6, J 7.7 Hz); 7.48 (t, 1H, H-7, J 7.7 Hz);
8.00 (d, 1H, H-5, J 7.8 Hz); 8.69 (s, 1H, NCHO); 10.30 (s, 1H, CHO) ppm. 13C-NMR (75.47 MHz; CDCl3):
δ
50.2 (C-2); 55.2 (40-OCH3); 114.0 (C-30,50); 118.4 (C-8); 126.0 (C-6); 127.4 (C-4a); 127.6 (C-5); 128.5
(C-20,60); 129.5 (C-10); 131.7 (C-3); 133.4 (C-7); 136.7 (C-8a); 142.8 (C-4); 159.6 (C-40); 160.5 (1-NCHO);
187.8 (3-CHO) ppm. MS (ESI+) m/z (%): 350.1 35Cl [M + Na]+ (100); 352,1 37Cl [M + Na]+ (40).
4-Chloro-2-(4-nitrophenyl)-1,2-dihydroquinoline-1,3-dicarbaldehyde (2f). Orange solid,
η
40%,
m.p. 151–153 ◦C. 1H-NMR (300.13 MHz; CDCl3):
δ 7.00 (s, 1H, H-2); 7.19 (d, 1H, H-8, J 7.9 Hz); 7.37 (d,
2H, H-20,60, J 8.8 Hz); 7.42 (t, 1H, H-6, J 7.6 Hz); 7.54 (t, 1H, H-7, J 7.6 Hz); 8.03 (d, 1H, H-5, J 7.9 Hz);
8.07 (d, 2H, H-30,50, J 8.8 Hz); 8.72 (s, 1H, 1-NCHO); 10.33 (s, 1H, 3-CHO) ppm. 13C-NMR (75.47 MHz;
CDCl3):
δ
50.5 (C-2); 118.4 (C-8); 123.8 (C-4a); 124.0 (C-30,50); 126.5 (C-6); 128.0 (C-5); 128.1 (C-20,60);
130.0 (C-3); 134.0 (C-7); 136.3 (C-8a); 144.0 (C-4); 144.1 (C-10); 147.8 (C-40); 160.6 (1-NCHO); 187.6
(3-CHO) ppm. MS (ESI+) m/z (%): 343.1 35Cl [M + H]+ (15); 345.1 37Cl [M + H]+ (2); 381.3 35Cl [M + K]+
(100); 383,0 37Cl [M + K]+ (15). EI-HRMS: calcd. for (C17H11N2O435Cl) 342.0407; found 342.0415. Calcd
for (C17H11N2O437Cl) 344.0378; found 344.0391.
3.3. General Procedures for the Synthesis of the Chromene-Indole Hybrids 4a–c
An excess of indole
the appropriate 2-aryl-4-chloro-2H-chromene-3-carbaldehyde 2a
DMSO (2.5 mL). The mixture was stirred and heated to 130 ◦C during 24 h. At the end, the reaction
3
(94 mg, 0.80 mmol) was added to a round bottom flask along with
–
c
(0.26 mmol) and dissolved in

Molecules 2020, 25, 3791
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mixture was poured into a mixture of ice/water (10 g/20 mL) and liquid-liquid extraction was performed
with dichloromethane (3 30 mL). The organic layer dried over anhydrous sodium sulfate, solvent
×
evaporated and the residue purified by thin layer chromatography using CH2Cl2 as eluent.
3,30-[(4-C◦hloro-2-phenyl-2H-chromen-3-yl)methylene]bis(1H-indole) (4a). Yellow solid,
η 79%,
1
m.p. 106-107 C. H-NMR (500.13 MHz; CDCl3):
δ
5.94 (s, 1H, H-200); 6.25 (s, 1H, 300-CHCroInd);
6.41 (d, 1H, H-2, J 2.0 Hz); 6.65–6.69 (m, 3H, H-800, 3000, 5000); 6.73–6.80 (m, 3H, H-2000, 4000, 6000); 6.92–7.03
(m, 5H, H-600, 5, 6, 7, 50); 7.89 (dt, 1H, H-700, J 1.6 and 7.8 Hz); 7.17 (dt, 1H, H-60, J 1.0 and 7.9 Hz);
7.25–7.29 (m, 1H, H-40); 7.37 (d, 1H, H-70, J 7.9 Hz); 7.50 (d, 1H, H-20, J 1.5 Hz); 7.53–7.56 (m, 1H, H-4);
7.64 (dd, 1H, H-500, J 1.6 and 7.8 Hz); 10.32 (d, 1H, H-1); 11.10 (large s, 1H, H-10) ppm. 13C-NMR
(125.77 MHz; CDCl3):
(C-30); 116.7 (C-800); 119.2 (2C, C-5, 50); 119.3 (C-4); 120.6 (C-40); 121.5 (C-6); 121.8 (C-600); 122.2 (C-60);
122.8 (C-20); 123.1 (C-400a); 123.7 (C-2); 124.8 (C-500); 125.0 (C-400); 126.9 (C-30a); 127.2 (C-3000, 5000
δ
36.2 (300-CHCroInd); 79.0 (C-200); 110.6 (C-7); 111.2 (C-70); 114.0 (C-3); 115.7
,
3a); 127.4 (C-2000, 6000); 127.6 (C-4000); 130.0 (C-700); 132.1 (C-300); 135.9 (C-7a); 136.6 (C-1000); 136.9
(C-70a); 152.4 (C-800a) ppm. ESI+-MS m/z (%): 509.2 35Cl [M + Na]+ (100); 511.2 37Cl [M + Na]+ (25).
EI-HRMS: calcd. for (C32H23N2O35Cl) 486.1499; found 486.1490. Calcd for (C32H23N2O37Cl) 488.1470;
found 488.1465.
3,30-[(4-chloro-2-(4-methoxyphenyl)-2H-chromen-3-yl)methylene]bis(1H-indole) (4b). red solid,
84%, m.p. 119–121 ◦C. 1H-NMR (500.13 MHz, DMSO-D6): 3.50 (s, 3H, 4000-OCH3); 6.01 (s, 1H, H-200);
η
δ
6.15 (s, 1H, 300-CHCroInd); 6.30 (d, 2H, H-3000, 5000, J 8.6 Hz); 6.65 (d, 1H, H-2, J 2.0 Hz); 6.65–6.67 (m,
1H, H-800); 6.71 (d, 2H, H-2000, 6000, J 8.6 Hz); 6.87 (t, 1H, H-50, J 7.5 Hz); 6.89–7.01 (m, 3H, H- 600, 5, 6);
7.04–7.10 (m, 2H, H-7, 60); 7.13 (dt, 1H, H- 700, J 1.0 and 7.7 Hz); 7.24 (d, 1H, H-40, J 8.0 Hz); 7.35 (d,
1H, H-20, J 1.5 Hz); 7.41 (d, 1H, H-70, J 8.1 Hz); 7.45 (d, 1H, H-4, J 8.1 Hz); 7.54 (dd, 1H, H-500, J 1.0
and 7.7 Hz); 10.57 (d, 1H, H-1, J 2.0 Hz); 11.06 (d, 1H, H-10, J 1.5 Hz) ppm. 13C-NMR (125.77 MHz,
DMSO-d6):
δ
35.6 (300-CHCroInd); 54.8 (4000-OCH3); 77.5 (C-200); 111.1 (C-7); 111.6 (C-70); 112.0 (C-3)
112.5 (C-3000, 5000); 114.3 (C- 30); 116.5 (C-800); 118.2 (C-40); 118.2 (C-5); 118.4 (C-50); 119.0 (C-4); 120.7
(C-6); 121.2 (C-60); 121.6 (C-600); 122.6 (C-400); 122.7 (C-400a); 123.2 (C-20); 124.3 (C-500, 2); 126.5 (C-30a);
127.0 (C-3a); 128.6 (C-2000, 6000); 128.8 (C-1000); 130.1 (C-700); 133.6 (C-300); 135.8 (C-7a); 136.6 (C-70a);
151.8 (C-800a); 158.6 (C-4000) ppm. ESI+-MS m/z (%): 539.2 35Cl [M + Na]+ (29); 541.2 37Cl [M + Na]+
(12). EI-HRMS: calcd. for (C33H25N2O235Cl) 516.1605; found 516.1610. Calcd for (C33H25N2O237Cl)
518.1575; found 518.1577.
3,30-[(4-Chloro-2-(4-nitrophenyl)-2H-chromen-3-yl)methylene]bis(1H-indole) (4c). Yellow solid,
60%, m.p. 179–180 ◦C. 1H-NMR (500.13 MHz, DMSO-d6): 6.14 (s, 1H, 300-CHCroInd); 6.26 (s, 1H,
η
δ
H-200); 6.69 (dd, 1H, H- 800, J 0.8 and 8.0 Hz); 6.75 (d, 1H, H-2, J 2.1 Hz); 6.82–6.94 (m, 6H, H-2000, 6000, 5,
6, 7, 50); 7.03–7.11 (m, 2H, H-600, 60); 7.17 (dt, 1H, H-700, J 1.6 and 8.0 Hz); 7.27 (d, 1H, H-40, J 8.0 Hz); 7.34
(d, 1H, H-4, J 7.4 Hz); 7.41–7.46 (m, 3H, H-3000, 5000, 70); 7.56 (d, 1H, H-20, J 1.6 Hz); 7.62 (dd, 1H, H-500,
J 1.6 and 7.8 Hz); 10.61 (d, 1H, H-1, J 2.1 Hz); 11.16 (d, 1H, H-10, J 1.6 Hz) ppm. 13C-NMR (125.77 MHz,
DMSO-d6):
δ
35.7 (300-CHCroInd); 77.1 (C-200); 111.4 (C-7); 112.1 (C-3); 112.1 (C-70); 113.8 (C-30); 116.9
(C-800); 118.6 (C-4); 118.9 (C-5, 50); 119.6 (C-40); 121.3 (C-6); 121.7 (C-60); 122.2 (C-3000, 5000); 122.4 (C-600);
122.6 (C-400a); 123.3 (C-20); 123.8 (C-400); 125.0 (C-500); 125.2 (C-2); 126.9 (C-30a); 127.1 (C-3a); 128.3
(C-2000, 6000); 131.0 (C-700); 133.5 (C-300); 136.2 (C-7a); 137.0 (C-70a); 143.2 (C-1000); 146.4 (C-4000); 151.7
(C-800a) ppm. ESI+-MS m/z (%): 554.2 35Cl [M + Na]+ (8); 556.2 37Cl [M + Na]+ (3). EI-HRMS: calcd. for
(C32H22N3O335Cl) 531.1350; found 531.1354. Calcd for (C32H22N3O337Cl) 533.1320; found 533.1327.
3.4. General Procedures for the Synthesis of 6-Aryl-6H-chromeno[3,4-c]quinolines 7a–f
In a round bottom flask with solution of the appropriate 2-aryl-4-chloro-2H-chromene-3-
carbaldehyde 2a
(0.27 mmol). The mixture was stirred at room temperature for 1.5 or 2.5 h depending on the substituents
in the 2-aryl-4-chloro-2H-chromene-3-carbaldehydes 2a . After this period, TFA (2.6 mmol in case of
–c (0.10 mmol) in dichloromethane (7 mL) was added the correspondent aniline 5
–c
3,4-dimethoxyanilinine and 26 mmol in case of aniline or 4-nitroaniline) was added to the reaction
mixture and left stirring at room temperature for 72 h. Finally, the solvent was evaporated on the rotary

Molecules 2020, 25, 3791
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evaporator and the mixture was purified by preparative chromatography using CH2Cl2 or a mixture
of CH2Cl2/hexane (3:1) as eluent.
1-[4-Chloro-2-phenyl-2H-chromen-3-yl)]-N-(3,4-dimethoxyphenyl)methanimine (6b). Yellow solid,
η
17%, m.p. 79–81 ◦C. 1H-NMR (500.13 MHz, CDCl3): 3.90 and 3.91 (s, 3H, 300- and 400-OCH3); 6.79
δ
(s, 1H, H-2), 6.81 (dd, 1H, H-600, J 2.3 and 6.0 Hz); 6.83 (d, 1H, H- 200, J 2.3 Hz); 6.86 (d, 1H, H-500,
J 6.0 Hz); 6.90 (dd, 1H, H-8, J 1.1 and 8.1 Hz); 6.99 (dt, 1H, H-6, J 1.0 and 7.8 Hz); 7.41 (d, 2H, H-20,60,
J 8.8 Hz); 7.21–7.28 (m, 4H, H-7,30,40,50); 7.63 (dd, 1H, H-5, J 1.5 and 7.8 Hz); 8.84 (s, 1H, CHN) ppm.
13C-NMR (125.77 MHz, CDCl3):
δ
56.0 and 56.1 (300- and 400-OCH3); 76.0 (C-2); 105.7 (C-600); 111.2
(C-500); 112.9 (C-200); 117.2 (C-8); 121.5 (C- 4a); 121.7 (C-6); 125.6 (C-5); 127.3 (C-20,60); 127.9 (C-3); 128.3
(C-30,40,50); 132.2 (C-7); 134.8 (C-4); 138.8 (C-10); 144.7 (C-100); 148.4 (C-400); 149.3 (C-300); 153.0 (CHN);
154.2 (C-8a) ppm. ESI+-MS m/z (%): 406.1 35Cl [M + H]+ (100); 408.1 37Cl [M + H]+ (52).
1-[4-Chloro-2-(4-nitrophenyl)-2H-chromen-3-yl)]-N-(3,4-dimethoxyphenyl)methanimine (6f).
◦
η 9%, m.p. 109–112 C. H-NMR (300.13 MHz, CDCl3): δ
3.91 and 3.92 (s, 3H, 300-
1
Yellow solid,
and 400-OCH3); 6.81 (t, 1H, H-200, J 2.0 Hz); 6.84–6.87 (m, 3H, H-2,600,500); 6.95 (dd, 1H, H-8, J 1.1
and 7.9 Hz); 7.03 (dt, 1H, H-6, J 1.1 and 7.9 Hz); 7.30 (dt, 1H, H-7, J 1.6 and 7.9 Hz); 7.59 (d, 2H, H-20,60,
J 8.8 Hz); 7.64 (dd, 1H, H-5, J 1.6 and 7.9 Hz); 8.11 (d, 1H, H-30,50, J 8.8 Hz); 8.87 (s, 1H, CHN) ppm.
13C-NMR (75.47 MHz, CDCl3):
δ
56.0 and 56.1 (300- and 400-OCH3); 75.0 (C-2); 105.5 (C-600); 111.3 (C-500);
113.2 (C-200); 117.1 (C-8); 121.1 (C- 4a); 122.3 (C-6); 123.5 (C-30,50); 125.9 (C-5); 127.1 (C-3); 128.1 (C-20,60);
132.7 (C- 7); 135.4 (C-4); 144.1 (C-100); 146.1 (C-10); 147.7 (C-40); 148.8 (C-300); 149.5 (C-400); 152.5 (CHN);
153.7 (C-8a) ppm. ESI+-MS m/z (%): 451.1 35Cl [M + H]+ (100); 453.1 37Cl [M + H]+ (30).
1
6-Phenyl-6H-chromeno[3,4-c]quinoline (7a). Yellow oil,
η
40%. H-NMR (500,13 MHz, CDCl3):
δ
6.37 (s, 1H, H-6); 7.05 (dd, 1H, H-4, J 1.3 and 7.9 Hz); 7.18 (dt, 1H, H-2, J 1.3 and 7.5 Hz); 7.39 (dt,
1H, H-3, J 1.3 and 7.5 Hz); 7.41–7.50 (m, 7H, H-7,11, 20,30,40,50,60); 7.66 (d, 1H, H-12, J 8.3 Hz); 7.70
(dt, 1H, H-10, J 1.4 and 7.0 Hz); 8.15 (d, 1H, H-9, J 8.3 Hz); 8.50 (dd, 1H, H-1, J 1.3 and 7.9 Hz) ppm.
13C-NMR (500,13 MHz, CDCl3):
δ 80.3 (C-6); 117.7 (C-4); 122.6 (C-2); 123.2 (C-12c); 125.6 (C-1); 126.3
(C-11); 126.5 (C-6a); 127.5 (C-12a); 127.8 (C-12); 128.2 (C-20,60); 128.8 (C-30,50); 129.0 (C-40); 129.3 (C-9);
129.8 (C-10); 132.0 (C-3); 132.9 (C-7); 138.6 (C-10); 148.1 (C-8a); 148.9 (C-12b); 156.6 (C-4a) ppm. ESI+-MS
m/z (%):310.2 [M + H]+ (42).
10,11-Dimethoxy-3-phenyl-3H-chromene[3,4-c]quinoline (7b). Yellow solid,
η
63%, m.p. 127–128 ◦C.
3.95 (s, 3H, 11-OCH3); 4.07 (s, 3H, 10-OCH3); 6.34 (s, 1H, H-6); 6.91 (s,
1H-NMR (500.13 MHz, CDCl3):
δ
1H, H-12); 7.04 (dd, 1H, H-4, J 1.0 and 8.1 Hz); 7.16 (dt, 1H, H-2, J 1.0 and 7.6 Hz); 7.30 (s, 1H, H-7);
7.35 (ddd, 1H, H-3, J 1.6; 7.6 and 8.1 Hz); 7.40–7.52 (m, 6H, H-9,20,30,40,50,60); 8.45 (dd, 1H, H-1, J 1.6
and 7.6 Hz) ppm. 13C-NMR (125.77 MHz, CDCl3):
δ 56.0 (11-OCH3); 56.2 (10-OCH3); 80.4 (C-6); 105.0
(C-12a); 105.3 (C-12); 107.9 (C-9); 117.6 (C-4); 122.5 (C-2); 123.1 (C-12c); 125.0 (C-1); 126.7 (C-6a); 128.3
(C-20,60); 128.8 (C-30,50); 128.9 (C-40); 131.2 (C-3); 131.4 (C-7); 139.0 (C-10); 145.1 (C-8a); 146.8 (C-12b);
149.7 (C-11); 152.7 (C-10); 156.1 (C-4a) ppm. ESI+-MS m/z (%): 370.1 [M + H]+ (100). EI-HRMS: calcd.
for (C24H19NO3) 369.1365; found 369.1368.
1
10-Nitro-3-phenyl-3H-chromeno[3,4-c]quinoline (7c). Orange oil,
CDCl3):
20,30,40,50,60), 7.60 (s, 1H, H-7); 8.26 (d, 1H, H-9, J 9.1 Hz); 8.45 (dd, 1H, H-10, J 2.4 and 9.1 Hz); 8.55 (d,
η
25%. H-NMR (500,13 MHz,
δ
6.38 (s, 1H, H-6); 7.09 (d, 1H, H-4, J 8.0 Hz); 7.20–7.26 (m, 1H, H-2); 7.44–7.49 (m, 6H, H-3,
1H, H-1, J 7.5 Hz); 8.62 (d, 1H, H-12, J 2.4 Hz) ppm. 13C-NMR (500,13 MHz, CDCl3):
δ 80.2 (C-6); 118.0
(C-4); 122.2 (C-12a); 122.6 (C-2); 123.1 (C-10); 123.5 (C-6a); 124.6 (C-12); 126.4 (C-1); 128.2 (C-20,60); 128.6
(C-12c); 129.1 (C-30,50); 129.4 (C-40); 130.8 (C-9); 133.5 (C-3); 134.5 (C-7); 137.8 (C-10); 145.1 (C-11); 150.2
(C-8a); 152.4 (C-12b); 157.2 (C-4a) ppm. ESI+-MS m/z (%):355.2 [M + H]+ (100).
1
3-(4-Methoxyphenyl)-3H-chromeno[3,4-c]quinoline (7d). Yellow oil,
η
50%. H-NMR (500,13 MHz,
CDCl3):
δ
3.84 (s, 3H, 40-OCH3); 6.32 (s, 1H, H-6); 6.96 (d, 2H, H-30,50, J 8.8 Hz); 7.03 (d, 1H, H-4, J
9.2 Hz); 7.17 (t, 1H, H-2, J 7.5 Hz); 7.33–7.50 (m, 5H, H-3, 7, 11, 20,60); 7.65 (d, 1H, H-12, J 7.8 Hz); 7.69 (t,
1H, H-10, J 7.7 Hz); 8.14 (d, 1H, H-9, J 7.8 Hz); 8.52 (d, 1H, H-1, J 9.2 Hz) ppm. 13C-NMR (500,13 MHz,
CDCl3):
126.2 (C-11); 127.6 (C-12); 127,7 (C-12a); 128.8 (C-12); 129.3 (C-10); 129.7 (C-20,60); 129.7 (C-10); 130.8
δ
55.4 (40-OCH3); 80.0 (C-6); 114.2 (C-30,50); 117.7 (C-4); 122.5 (C-2); 123.5 (C-12c); 125.5 (C-1);

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(C-10); 132.0 (C-3); 132.9 (C-7); 148.1 (C-8a); 149.0 (C-12b); 156.5 (C-4a); 160.0 (C-40) ppm. ESI+-MS m/z
(%): 340.2 [M + H]+ (100).
10,11-Dimethoxy-3-(4-methoxyphenyl)-3H-chromene[3,4-c]quinoline (7e). Yellow solid,
η 75%,
m.p. 107–108 ◦C. 1H-NMR (300.13 MHz, acetone-d6):
δ
3.82 (s, 3H, 40-OCH3); 3.93 (s, 3H, 11-OCH3);
4.02 (s, 3H, 10-OCH3); 6.42 (s, 1H, H-6); 6.94–7.02 (m, 3H, H-4,30,50); 7.14 (dt, 1H, H-2, J 1.1 and 7.7 Hz);
7.20 (s, 1H, H-12); 7.32–7.43 (m, 3H, H-3,20,60); 7.44 (s, 1H, H-9); 7.53 (s, 1H, H-7); 8.44 (dd, 1H, H-1,
J 1.6 and 7.7 Hz) ppm. 13C-NMR (75.47 MHz, acetone-d6):
δ
55.5 (40-OCH3); 56.1 (10- and 11-OCH3);
80.2 (C-6); 106.4 (C-9); 108.5 (C-12); 114.7 (C-30,50); 118.3 (C-4); 122.8 (C-2); 124.1 (C-12a); 124.5 (C-12c);
125.6 (C-1); 127.3 (C-6a); 130.3 (C- 20,60); 131.9 (C-3,7); 132.5 (C-10); 145.9 (C-8a); 146.8 (C-12b); 151.0
(C-11); 154.0 (C-10); 156.9 (C-4a); 160.8 (C-40) ppm. ESI+-MS m/z (%): 400.1 [M + H]+ (100). EI-HRMS:
calcd. for (C25H21NO4) 399.1471; found 399.1475.
10,11-Dimethoxy-3-(4-nitrophenyl)-3H-chromene[3,4-c]quinoline (7f). Yellow solid,
η 73%, m.p.
149–150 ◦C. 1H-NMR (300.13 MHz, CDCl3):
δ
3.97 (s, 3H, 10-OCH3); 4.07 (s, 3H, 11-OCH3); 6.44 (s, 1H,
H-6); 6.93 (s, 1H, H-9); 7.04 (dd, 1H, H-4, J 1.0 and 7.8 Hz); 7.18 (dt, 1H, H-2, J 1.0 and 7.8 Hz); 7.32 (s,
1H, H-7); 7.37 (dt, 1H, H-3, J 1.6 and 7.8 Hz); 7.50 (s, 1H, H-12); 7.65 (d, 2H, H-20,60, J 8.8 Hz); 8.28 (d,
2H, H-30,50, J 8.8 Hz); 8.44 (dd, 1H, H-1, J 1.6 and 7.8 Hz) ppm. 13C-NMR (75.47 MHz, CDCl3):
δ 56.1
(10- OCH3); 56.3 (11-OCH3); 78.9 (C-6); 105.2 (C-9); 107.9 (C-12); 117.6 (C-4); 123.0 (C-12a); 123.0 (C-2);
123.3 (C-12c); 123.9 (C-30,50); 125.0 (C-6a); 125.1 (C-1); 128.9 (C-20,60); 131.0 (C-7); 131.6 (C-3); 145.4
(C-8a); 146.1 (C-10); 146.2 (C-12b); 148.1 (C-40); 150.0 (C- 10); 153.0 (C-11); 155.3 (C-4a) ppm. ESI+-MS
m/z (%):415.1 [M + H]+ (100). EI-HRMS: calcd. for (C24H18N2O5) 414.1216; found 414.1219.
3.5. General Procedures for the Synthesis of the (Z)-and (E)-2-aryl-4-chloro-3-styryl-2H-chromenes
10a–i/11a–i
A mixture of appropriate phosphonium halide (8a
and NaH (13 mg, 0.5 mmol) was stirred under reflux until formation of the corresponding ylide, then,
the 4-chloro-2-phenyl-2H-chromene-3-carbaldehydes 2a (0.07 mmol) was added and the reaction
–c, 77 mg, 0.21 mmol) in freshly dry THF (10 mL)
–
c
mixture continued in reflux (or room temperature). At the end, the reaction mixture was poured into
a mixture of ice (10 g) and water (20 mL) and acidified at pH ~3 with a solution HCl (10%). Then,
extracted with ethyl acetate (3
the solvent was evaporated to dryness and the solid residue was purified by thin layer chromatography
×
20 mL), the organic layer was dried over anhydrous sodium sulphate,
using as eluent a mixtures dichloromethane/hexane.
(Z)-4-Chloro-2-phenyl-3-styryl-2H-chromene (10a). White solid,
5.89 (s, 1H, H-2); 6.37 (d, 1H, H-
η
32%, m. p. 112–113 ◦C. 1H-NMR
, J 12.3 Hz); 6.64 (d, 1H, H- , J 12.3 Hz); 6.76 (dd,
(300.13 MHz; CDCl3):
δ
α
β
1H, H-8, J 1.3 and 8.0 Hz); 6.95 (ddd, 1H, H-6, J 1.3, 7.1 and 8.0 Hz); 7.14–7.22 (m, 6H, H-20,30,40,50,60,7);
7.31–7.43 (m, 5H, H-200,300, 400,500,600); 7.55 (dd, 1H, H-5, J 1.3 and 8.0 Hz) ppm. 13C-NMR (75.47 MHz;
CDCl3):
δ 78.2 (C-2); 116.4 (C-8); 121.3 (C-4a); 121.4 (C-6); 124.5 (C-β); 124.6 (C-5); 126.8 (C-4); 127.2
(C-20,60); 128.1 (C-40); 128.3 (C-30,50); 128.4 (C-400); 128.5 (C-200,600); 128.6 (C-300,500); 128.7 (C-10); 129.1
(C-3); 130.4 (C-7); 133.3 (C-α
); 136.7 (C-100); 152.7 (C-8a) ppm. ESI+-MS m/z (%): 367.1 Cl35 [M + Na]+
(45), 369.1 Cl37 [M + Na]+ (15). EI-HRMS m/z calcd for (C23H1735ClO) 344.0968, found 344.0964. Calcd
for (C23H1737ClO) 346.0938, found 346.0933.
(E)-4-Chloro-2-phenyl-3-styryl-2H-chromene (11a). White solid,
(300.13 MHz; CDCl3): 6.33 (s, 1H, H-2); 6.49 (d, 1H, H- , J 16.5 Hz); 6.79 (dd, 1H, H-8, J 1.3 and 8.0 Hz);
6.94 (ddd, 1H, H-6, J 1.3, 7.1 and 8.0 Hz); 7.13 (ddd, 1H, H-7, J 1.3, 7.1 and 8.0 Hz); 7.25–7.34 (m, 6H,
H-200,300,400,500,600,40); 7.39–7.45 (m, 4H, H-20,30,50,60); 7.56 (d, 1H, H-
, J 16.5 Hz); 7.57 (dd, 1H, H-5, J 1.3
and 8.0 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3):
77.4 (C-2); 116.7 (C-8); 121.7 (C-6); 122.2 (C-4a);
η
25%, m. p. 121–123 ◦C. 1H-NMR
δ
β
α
δ
123.2 (C-α
); 125.0 (C-5); 126.8 (C-200,600); 127.2 (C-4); 127.7 (C-20,60); 128.3 (C-40); 128.5 (C-300,500); 128.7
(C-30,50); 130.4 (C-7); 131.8 (C-β); 136.7 (C-3); 137.7 (C-10); 152.2 (C-8a) ppm.
(Z)-4-Chloro-3-(4-ethoxyvinyl)-2-phenyl-2H-chromene (10b). White solid,
η
45%, m. p. 100–102 ◦C.
1H-NMR (300.13 MHz; CDCl3):
δ
1.42 (t, 3H, 400-OCH2CH3, J 7.0 Hz); 4.05 (qd, 2H, 40-OCH2CH3,
J 1.7 and 7.0 Hz); 5.95 (s, 1H, H-2); 6.24 (d, 1H, H-
α
, J 12.2 Hz); 6.58 (d, 1H, H- , J 12.2 Hz); 6.77 (dd, 1H,
β

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H-8, J 1.1 and 7.8 Hz); 6.87 (d, 2H, H-300,500, J 9.0 Hz); 6.95 (dt, 1H, H-6, J 1.1 and 7.6 Hz); 7.15 (dt, 1H,
H-7, J 1.1 and 7.6 Hz); 7.19–7.23 (m, 5H, H-20,30,40,50,60); 7.37 (d, 2H, H-200,600, J 9.0 Hz); 7.54 (dd, 1H,
H-5, J 1.1 and 7.8 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3):
δ
14.8 (400-OCH2CH3); 63.4 (400-OCH2CH3);
); 124.5 (C-5); 126.3 (C-4);
127.2 (C-20,60); 128.2 (C-30,50); 128.4 (C-40); 129.1 (C-10); 129.5 (C-3); 130.1 (C-200,600); 130.2 (C-7); 132.9
78.2 (C-2); 114.4 (C-300,500); 116.3 (C-8); 121.4 (C-6); 121.5 (C-4a); 122.7 (C-
α
(C-β
); 138.9 (C-100); 152.6 (C-8a); 158.8 (C-400) ppm. ESI+-MS m/z (%): 411.1 Cl35 [M + Na]+ (100);
413.1 Cl37 [M + Na]+ (3). EI-HRMS m/z calcd for (C25H2135ClO2) 388.1230, found 388.1226. Calcd for
(C25H2137ClO2) 390.1201, found 390.1216.
(E)-4-Chloro-3-(4-ethoxyvinyl)-2-phenyl-2H-chromene (11b). Yellow solid,
1H-NMR (300.13 MHz; CDCl3): 1.41 (t, 3H, 400-OCH2CH3, J 7.0 Hz); 4.02 (q, 2H, 40-OCH2CH3, J 7.0 Hz);
6.31 (s, 1H, H-2); 6.44 (d, 1H, H-
, J 16.5 Hz); 6.78 (d largo, 1H, H-8, J 8.0 Hz); 6.85 (d, 2H, H-300,500,
J 9.1 Hz); 6.94 (dt, 1H, H-6, J 1.4 and 7.7 Hz); 7.11 (dt, 1H, H-7, J 1.4 and 7.7 Hz); 7.26–7.29 (m, 3H,
H-30,40,50); 7.37 (d, 2H, H-200,600, J 9.1 Hz); 7.39–7.42 (m, 2H, H-20,60); 7.42 (d, 1H, H-
, J 16.5 Hz);
7.55 (dd, 1H, H-5, J 1.4 and 8.0 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3): 14.8 (400-OCH2CH3); 63.5
η
25%, m. p. 166–167 ◦C.
δ
β
α
δ
(400-OCH2CH3); 77.1 (C-2); 114.7 (C-300,500); 116.6 (C-8); 121.0 (C-
α); 121.6 (C-6); 122.4 (C-4a); 124.9 (C-5);
125.8 (C-4); 127.7 (C-30,50); 127.8 (C-3); 128.1 (C-200,600); 128.4 (C-100); 128.5 (C-20,60); 128.6 (C-40); 129.4
(C-10); 130.0 (C-7); 131.5 (C-β); 137.8 (C-3); 152.1 (C-8a); 159.3 (C-400) ppm.
(Z)-4-Chloro-2-phenyl-3-(4-nitrovinyl)-2H-chromene (10c). Yellow solid,
η
41%, m. p. 159–161 ◦C.
1H-NMR (300.13 MHz; CDCl3):
δ
5.78 (s, 1H, H-2); 6.53 (d, 1H, H- , J 12.2 Hz); 6.66 (d, 1H, H-β,
α
J 12.2 Hz); 6.79 (dd, 1H, H-8, J 1.2 and 7.9 Hz); 6.97 (dt, 1H, H-6, J 1.2 and 7.6 Hz); 7.16–7.25 (m, 6H,
H-7, 20,30,40,50,60); 7.53 (d, 2H, H-200,600, J 8.8 Hz); 7.55 (d, 1H, H-5, J 7.9 Hz); 8.17 (d, 2H, H-300,500,
J 8.8 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3):
δ
78.5 (C-2); 116.5 (C-8); 121.7 (C-6); 121.9 (C-4a);
123.8 (C-300,500); 125.5 (C-5); 127.2 (C-20,60); 127.6 (C-4); 128.3 (C- ); 128.5 (C-30,50); 128.7 (C-40); 129.0
β
(C-10); 129.2 (C-200,600); 130.9 (C- ); 131.0 (C-7); 138.2 (C-3); 143.3 (C-100); 147.0 (C-400); 152.4 (C-8a) ppm.
α
ESI+-MS m/z (%): 413.3 Cl35 [M + Na]+ (100), 415.3 Cl37 [M + Na]+ (30). Anal. Calcd for C23H16ClNO3:
C, 70,86%; H, 4,14%; N, 3,59%. Found: C, 71,19%; H, 4,16%; N, 3,53%.
(E)-4-Chloro-2-phenyl-3-(4-nitrovinyl)-2H-chromene (11c). Yellow solid,
η
33%, m. p. 194–196 ◦C.
1H-NMR (300.13 MHz; CDCl3):
δ
6.32 (s, 1H, H-2); 6.50 (d, 1H, H- , J 16.5 Hz); 6.80 (dd, 1H, H-8,
β
J 1.3 and 8.0 Hz); 6.97 (ddd, 1H, H-6, J 1.3, 7.2 and 8.0 Hz); 7.18 (ddd, 1H, H-7, J 1.3, 7.2 and 8.0 Hz);
7.28–7.33 (m, 3H, H-30,40,50); 7.39-7.42 (m, 2H, H-20,60); 7.56 (d, 2H, H-200,600, J 9.0 Hz); 7.60 (dd, 1H,
H-5, J 1.3 and 8.0 Hz); 7.71 (d, 1H, H-α
, J 16.5 Hz); 8.18 (d, 2H, H-300,500, J 9.0 Hz) ppm. 13C-NMR
(75.47 MHz; CDCl3):
δ
77.2 (C-2); 116.9 (C-8); 121.7 0(C-4a); 121.9 (C-6); 124.1 (C-300,500); 125.5 (C-5);
126.4 (C-4); 127.2 (C-200,600); 127.3 (C- ); 127.6 (C-20,6 ); 128.7 (C-30,50); 128.8 (C-40); 129.0 (C-
α β); 129.2
(C-10); 131.0 (C-7); 137.2 (C-3); 143.1 (C-100); 146.8 (C-400); 152.5 (C-8a) ppm.
(Z)-4-Chloro-2-(4-methoxyphenyl)-3-vinyl-2H-chromene (10d). Yellow solid,
η
50%, m. p. 78–80 ◦C.
, J 12.2 Hz);
, J 12.2 Hz); 6.72 (dlargo, 1H, H-8, J 8.0 Hz); 6.73 (d, 2H, H-30,50, J 8.9 Hz); 6.95 (dt, 1H,
H-6, J 1.2 and 7.6 Hz); 7.06 (d, 2H, H-20,60, J 8.9 Hz); 7.11 (dt, 1H, H-7, J 1.2 and 7.6 Hz); 7.29–7.42 (m,
5H, H-200,300,400,500,600); 7.55 (dd, 1H, H-5, J 1.2 and 8.0 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3):
55.1
(40-OCH3); 77.9 (C-2); 113.6 (C-30,50); 116.4 (C-8); 121.3 (C-6); 121.4 (C-4a); 124.4 (C-
); 124.5 (C-5); 126.8
(C-4); 128.1 (C-400); 128.5 (C-300,500); 128.6 (C-200,600); 128.7 (C-20,60); 129.3 (C-3); 130.3 (C-7); 130.8 (C-10);
1H-NMR (300.13 MHz; CDCl3):
δ α
3.73 (s, 3H, 40-OCH3); 5.83 (s, 1H, H-2); 6.35 (d, 1H, H-
6.63 (d, 1H, H-
β
δ
α
133.3 (C-β
); 136.7 (C-100); 152.5 (C-8a); 159.7 (C-40) ppm. ESI+-MS m/z (%): 413.1 Cl35 [M + K]+ (10).
EI-HRMS m/z calcd for (C24H1935ClO2) 374.1074; found 374.1082. Calcd for (C24H1937ClO2) 376.1044;
found 376.1050.
(E)-4-Chloro-2-(4-methoxyphenyl)-3-vinyl-2H-chromene (11d). White solid,
η
28%, m. p. 187–189 ◦C.
3.73 (s, 3H, 40-OCH3); 6.28 (s, 1H, H-2); 6.47 (d, 1H, H-
δ β, J 16.5 Hz);
1H-NMR (300.13 MHz; CDCl3):
6.77 (dd, 1H, H-8, J 1.4 and 8.3 Hz); 6.80 (d, 2H, H-30,50, J 8.7 Hz); 6.95 (dt, 1H, H-6, J 1.4 and 7.6 Hz);
7.13 (dt, 1H, H-7, J 1.4 and 7.6 Hz); 7.24–7.29 (m, 1H, H-400); 7.31-7.35 (m, 4H, H-20,60,300,500); 7.42–7.45
(m, 2H, H-200,600); 7.44 (d, 2H, H-20,60, J 8.7 Hz); 7.53 (d, 1H, H-
α
, J 16.5 Hz); 7.58 (dd, 1H, H-5, J 1.4
and 8.3 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3):
δ
55.1 (40-OCH3); 76.9 (C-2); 113.9 (C-30,50); 116.7 (C-8);

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121.6 (C-6); 122.2 (C-4a); 123.0 (C-
α
); 125.0 (C-5); 126.8 (C-200,600); 127.4 (C-4); 128.3 (C-400); 128.5 (C-3); 128.7
(C-20,60); 129.1 (C-300,500); 129.8 (C-10); 130.3 (C-7); 131.8 (C- ); 136.7 (C-100); 152.2 (C-8a); 159.8 (C-40) ppm.
β
(Z)-4-Chloro-3-(4-ethoxyvinyl)-2-(4-methoxyphenyl)-2H-chromene (10e). Yellow oil,
η 30%.
1H-NMR (300.13 MHz; CDCl3): 1.43 (t, 3H, 400-OCH2CH3, J 7.0 Hz); 3.73 (s, 1H, 40-OCH3); 4.05 (q,
δ
2H, 400-OCH2CH3, J 7.0 Hz); 5.89 (s, 1H, H-2); 6.22 (d, 1H, H-
α, J 12.1 Hz); 6.56 (d, 1H, H-β, J 12.1 Hz);
6.72–6.75 (m, 3H, H-8,30,50); 6.87 (d, 2H, H-300,500, J 8.9 Hz); 6.95 (dt, 1H, H-6, J 1.4 and 7.7 Hz); 7.09 (d,
2H, H-20,60, J 8.9 Hz); 7.14 (dt, 1H, H-7, J 1.4 and 7.7 Hz); 7.36 (d, 2H, H-200,600, J 8.9 Hz); 7.55 (dd,1H,
H-5, J 1.4 and 8.0 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3):
δ
14.8 (400-OCH2CH3); 55.1 (40-OCH3);
63.4 (400-OCH2CH3); 77.9 (C-2); 113.6 (C-30,50); 114.6 (C-300,500); 116.4 (C-8); 121.3 (C-6); 121.4 (C-4a);
122.6 (C-
); 124.4 (C-5); 126.2 (C-4); 128.7 (C-20,60); 129.1 (C-100); 129.7 (C-3); 130.0 (C-200,600); 130.2 (C-7);
130.9 (C-10); 132.9 (C-
α
β
); 152.5 (C-8a); 158.8 (C-400); 159.6 (C-40) ppm. ESI+-MS m/z (%): 441.2 Cl35
[M + Na]+ (10); 443.2 Cl37 [M + Na]+ (10). Anal. Calcd for C26H23ClO3: C, 74.55%; H, 5.53%. Found C,
74.73%; H, 5.55%.
(E)-4-Chloro-3-(4-ethoxyvinyl)-2-(4-methoxyphenyl)-2H-chromene (11e). Yellow solid,
m. p. 140–142 ◦C. 1H-NMR (300.13 MHz; CDCl3): 1.41 (t, 3H, 400-OCH2CH3, J 7.0 Hz); 3.73 (s, 1H,
, J 16.5 Hz); 6.76 (dd,
η 20%,
δ
40-OCH3); 4.03 (q, 2H, 400-OCH2CH3, J 7.0 Hz); 6.26 (s, 1H, H-2); 6.42 (d, 1H, H-
β
1H, H-8, J 1.3 and 8.0 Hz); 6.79 (d, 2H, H-30,50, J 8.8 Hz); 6.84 (d, 2H, H-300,500, J 8.8 Hz); 6.93 (dt, 1H, H-6,
J 1.3 and 7.6 Hz); 7.11 (dt, 1H, H-7, J 1.3 and 7.6 Hz); 7.32 (d, 2H, H-20,60, J 8.8 Hz); 7.37 (d, 2H, H-200,600,
J 8.8 Hz); 7.42 (d, 1H, H-
CDCl3):
14.7 (400-OCH2CH3); 55.1 (40-OCH3); 63.5 (400-OCH2CH3); 76.9 (C-2); 113.8 (C-30,50); 114.6
(C-300,500); 116.6 (C-8); 120.9 (C-
α
, J 16.5 Hz); 7.56 (dd, 1H, H-5, J 1.3 and 8.0 Hz) ppm. 13C-NMR (75.47 MHz;
δ
α
); 121.5 (C-6); 122.4 (C-4a); 124.8 (C-5); 127.7 (C-4); 128.1 (C-200,600);
128.7 (C-3); 129.1 (C-20,60); 129.4 (C-100); 129.9 (C-10); 130.0 (C-7); 131.4 (C-
159.7 (C-40) ppm.
β
); 152.0 (C-8a); 159.2 (C-400);
1
(Z)-4-Choro-2-(4-methoxyphenyl)-3-(4-nitrovinyl)-2H-chromene (10f). Yellow oil,
(300.13 MHz; CDCl3): 3.74 (s, 3H, 4-OCH3); 5.72 (s, 1H, H-2); 6.51 (d, 1H, H-
H-
η
53%. H-NMR
δ
α, J 12.3 Hz); 6.64 (d, 1H,
β
, J 12.3 Hz); 6.78 (dlargo, 1H, H-8, J 8.0 Hz); 6.82 (d, 2H, H-30,50, J 8.7 Hz); 6.97 (dt, 1H, H-6, J 1.3
and 7.6 Hz); 7.18 (td, 1H, H-7, J 1.3 and 7.6 Hz); 7.31 (d, 2H, H-20,60, J 8.7 Hz); 7.55 (d, 2H, H-200,600,
J 8.7 Hz); 7.61 (d, 1H, H-5, J 8.0 Hz); 8.17 (d, 2H, H-300,500, J 8.8 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3):
δ
55.2 (40-OCH3); 78.2 (C-2); 114.0 (C-30,50); 116.9 (C-8); 121.6 (C-4a); 121.8 (C-6); 124.1 (C-300,500); 125.4
(C-5); 126.5 (C-4); 127.1 (C-200,600); 127.2 (C-40); 128.2 (C- ); 129.0 (C-20,60); 129.2 (C-10); 129.3 (C-3);
α
131.0 (C-β
); 131.2 (C-7); 143.2 (C-100); 147.0 (C-400); 152.4 (C-8a); 160.0 (C-40) ppm. ESI+-MS m/z (%):
442.1 Cl35 [M + Na]+ (20); 444.1 Cl37 [M + Na]+ (10). EI-HRMS m/z calcd for (C24H18N35ClO4) 419.0924,
found 419.0932. Calcd for (C24H18N37ClO4) 421.0895, found 421.0895.
(E)-4-C◦hloro-2-(4-methoxyphenyl)-3-(4-nitrovinyl)-2H-chromene (11f). Yellow solid,
η 35%, m.
1
p. 170–172 C. H-NMR (300.13 MHz; CDCl3):
δ
3.75 (s, 3H, 40-OCH3); 6.27 (s, 1H, H-2); 6.47 (d,
1H, H-
H-6, J 1.3 and 7.6 Hz); 7.17 (dt, 1H, H-7, J 1.3 and 7.6 Hz); 7.31 (d, 2H, H-20,60, J 8.8 Hz); 7.55 (d, 2H,
H-200,600, J 8.8 Hz); 7.61 (dd, 1H, H-5, J 1.3 and 8.0 Hz); 7.68 (d, 1H, H- , J 16.6 Hz); 8.17 (d, 2H, H-300,500,
J 8.8 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3): 55.2 (40-OCH3); 76.8 (C-2); 114.0 (C-30,50); 116.9 (C-8);
121.6 (C-4a); 121.8 (C-6); 124.1 (C-300,500); 125.4 (C-5); 126.4 (C-4); 127.1 (C-20,60); 127.2 (C-
); 128.7 (C-3);
128.9 (C-
); 129.0 (C-200,600); 129.2 (C-10); 131.2 (C-7); 143.4 (C-100); 147.0 (C-400); 152.4 (C-8a); 160.0
(C-40) ppm.
(Z)-4-Chloro-2-(4-nitrophenyl)-3-vinyl-2H-chromene (10g). Red oil,
CDCl3): 5.30 (s, 1H, H-2); 6.48 (d, 1H, H- , J 12.2 Hz); 6.72 (d, 1H, H-
β
, J 16.6 Hz); 6.78 (dd, 1H, H-8, J 1.3 and 8.0 Hz); 6.82 (d, 2H, H-30,50, J 8.8 Hz); 6.97 (dt, 1H,
α
δ
α
β
1
η
34%. H-NMR (300.13 MHz;
, J 12.2 Hz); 6.80 (dd, 1H,
δ
α
β
H-8, J 1.3 and 8.0 Hz); 6.99 (dt, 1H, H-6, J 1.3 and 7.6 Hz); 7.20 (dt, 1H, H-7, J 1.3 and 7.6 Hz); 7.30 (d,
2H, H-20,60, J 9.0 Hz); 7.33-7.39 (m, 5H, H-200,300,400,500,600); 7.56 (dd, 1H, H-5, J 1.3 and 8.0 Hz); 8.05
(d, 2H, H-30,50, J 9.0 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3):
δ
77.3 (C-2); 116.2 (C-8); 121.0 (C-4a);
); 124.8 (C-5); 126.7 (C-3); 127.7 (C-4); 127.8 (C-20,60); 128.3 (C-400);
128.4 (C-300,500); 128.5 (C-200,600); 130.7 (C-7); 133.7 (C- ); 136.3 (C-100); 145.8 (C-40); 147.5 (C-10); 152.1
121.9 (C-6); 123.3 (C-30,50); 124.0 (C-
α
β

Molecules 2020, 25, 3791
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(C-8a) ppm. ESI+-MS m/z (%): 412.1 Cl35 [M + Na]+ (15); 414.3 Cl37 [M + Na]+ (10). EI-HRMS m/z calcd
for (C23H16N35ClO3) 389.0819, found 389.0817. Calcd for (C23H16N37ClO3) 391.0789; found 391.0804.
(E)-4-Chloro-2-(4-nitrophenyl)-3-vinyl-2H-chromene (11g). Orange oil,
(300.13 MHz; CDCl3): 6.38 (s, 1H, H-2); 6.48 (d, 1H, H- , J 16.5 Hz); 6.84 (dd, 1H, H-8, J 1.2
η
15%. 1H-NMR
δ
β
and 8.1 Hz); 6.99 (ddd, 1H, H-6, J 1.2, 7.0 and 8.1 Hz); 7.17 (ddd, 1H, H-7, J 1.2, 7.0 and 8.1 Hz); 7.28–7.37
(m, 5H, H-200,300,400,500,600); 7.57 (dlargo, 1H, H-5, J 8.1 Hz); 7.60 (d, 2H, H-20,60, J 9.0 Hz); 7.61 (d, 1H,
H-
(C-8); 122.0 (C-4a); 122.3 (C-6); 123.0 (C-
α δ 75.6 (C-2); 116.7
, J 16.5 Hz); 8.14 (d, 2H, H-30,50, J 9.0 Hz) ppm. 13C-NMR (75,47 MHz; CDCl3):
α
); 123.8 (C-20,60); 125.4 (C-5); 126.3 (C-4); 126.9 (C-200600); 127.7
(C-100); 128.7 (C-30,50); 128.8 (C-400); 128.9 (C-300,500); 130.8 (C-7); 132.0 (C-
β
); 136.3 (C-3); 144.9 (C-10);
148.0 (C-40); 151.8 (C-8a) ppm.
1
(Z)-4-Chloro-3-(4-ethoxyvinyl)-2-(4-nitrophenyl)-2H-chromene (10h). Yellow oil,
(300.13 MHz; CDCl3):
6.03 (s, 1H, H-2); 6.34 (d, 1H, H-
η
45%. H-NMR
δ
1.43 (t, 3H, 400-OCH2CH3, J 7.0 Hz); 4.06 (q, 2H, 400-OCH2CH3, J 7.0 Hz);
α
, J 12.1 Hz); 6.65 (d, 1H, H-
β, J 12.1 Hz); 6.82 (dd, 1H, H-8, J 1.3
and 8.0 Hz); 6.87 (d, 2H, H-300,500, J 9.0 Hz); 6.99 (dt, 1H, H-6, J 1.3 and 7.6 Hz); 7.20 (dt, 1H, H-7, J 1.3
and 7.6 Hz); 7.34 (d, 4H, H-20,60,200,600, J 9.0 Hz); 7.55 (dd, 1H, H-5, J 1.3 and 8.0 Hz); 8.05 (d, 2H, H-30,50,
J 9.0 Hz) ppm 13C-NMR (75.47 MHz; CDCl3):
δ
14.8 (400-OCH2CH3); 63.5 (400-OCH2CH3), 76.7 (C-2);
); 123.5 (C-30,50); 124.8 (C-5); 127.5 (C-3);
); 146.2 (C-40); 147.4
114.5 (C-300,500); 116.3 (C-8); 121.3 (C-4a); 122.0 (C-6); 122.3 (C-
α
127.9 (C-200,600); 128.3 (C-4); 128.7 (C-100); 130.1 (C-20,60); 130.7 (C-7); 133.6 (C-
β
(C-10); 152.2 (C-8a); 159.1 (C-400) ppm. ESI+-MS m/z (%): 456.1 35Cl [M + Na]+ (45); 458.1 37Cl [M + Na]+
(15). EI+-HRMS m/z calcd for (C25H20NO435Cl) 433.1081; found 433.1084. Calcd for (C25H20NO237Cl)
435.1051; found 435.1060.
1
(E)-4-Chloro-3-(4-ethoxyvinyl)-2-(4-nitrophenyl)-2H-chromene (11h). Yellow oil,
(300.13 MHz; CDCl3):
1H, H-2); 6.42 (d, 1H, H-
6.97 (dt, 1H, H-6, J 1.4 and 7.8 Hz); 7.15 (dt, 1H, H-7, J 1.4 and 7.8 Hz); 7.39 (d, 2H, H-200,600, J 9.0 Hz);
7.46 (d, 1H, H-
, J 16.5 Hz); 7.56 (d, 1H, H-5, J 1.4 and 8.0 Hz); 7.60 (d, 2H, H-20,60, J 9.0 Hz); 8.13 (d,
2H, H-30,50, J 9.0 Hz) ppm. 13C-NMR (75.47 MHz; CDCl3): 14.6 (400-OCH2CH3); 63.4 (400-OCH2CH3),
75.4 (C-2); 114.6 (C-300,500); 116.4 (C-8); 120.6 (C- ); 122.0 (C-4a); 122.1 (C-6); 123.6 (C-30,50); 125.0 (C-5);
η
24%. H-NMR
δ
1.43 (t, 3H, 400-OCH2CH3, J 7.0 Hz); 4.06 (q, 2H, 400-OCH2CH3, J 7.0 Hz); 6.36 (s,
, J 16.5 Hz); 6.83 (dd, 1H, H-8, J 1.4 and 8.0 Hz); 6.87 (d, 2H, H-300,500, J 9.0 Hz);
β
α
δ
α
126.2 (C-4); 126.4 (C-100); 128.1 (C-20,60); 128.5 (C-200,600); 128.7 (C-3); 130.2 (C-7); 131.5 (C-
(C-10); 147.8 (C-40); 151.4 (C-8a); 159.4 (C-400) ppm.
β
); 144.8
(Z)-4-Chloro-2-(4-nitrophenyl)-3-(4-nitrovinyl)-2H-chromene (10i). Orange solid,
163–165 ◦C. 1H-NMR (300.13 MHz; CDCl3):
5.85 (s, 1H, H-2); 6.63 (d, 1H, H- , J 12.2 Hz); 6.74 (d, 1H,
H-
η 52%, m. p.
δ
α
β
, J 12.2 Hz); 6.84 (dd, 1H, H-8, J 1.3 and 8.0 Hz); 7.01 (ddd, 1H, H-6, J 1.3, 7.3 and 8.0 Hz); 7.24 (ddd,
1H, H-7, J 1.3, 7.3 and 8.0 Hz); 7.36 (d, 2H, H-20,60, J 8.8 Hz); 7.56 (dd, 1H, H-5, J 1.3 and 8.0 Hz); 7.58 (d,
2H, H-200,600, J 8.8 Hz); 8.09 (d, 2H, H-30,50, J 8.8 Hz); 8.20 (d, 2H, H-300,500, J 8.8 Hz) ppm.13C-NMR
(75.47 MHz; CDCl3):
125.2 (C-5); 126.4 (C-3); 127.8 (C-
142.8 (C-100); 145.3 (C-10); 147.3 (C-400); 147.9 (C-40); 152.2 (C-8a) ppm. ESI+-MS m/z (%): 457.1 Cl35
[M + Na]+ (80); 459.1 Cl37 [M + Na]+ (15). EI-HRMS m/z calcd for (C23H15N235ClO5) 434.0669, found
434.0668. Calcd for (C23H15N237ClO5) 436.0640, found 436.0647.
δ
77.0 (C-2); 116.6 (C-8); 120.8 (C-4a); 122.4 (C-6); 123.7 (C-300,500); 124.0 (C-30,50);
α
); 127.9 (C-20,60); 128.6 (C-4); 129.3 (C-200,600); 131.3 (C-7); 131.5 (C-
β);
(E)-4-Chloro-2-(4-nitrophenyl)-3-(4-nitrovinyl)-2H-chromene (11i). Orange solid,
180–182 ◦C. 1H-NMR (300.13 MHz; CDCl3):
6.38 (s, 1H, H-2); 6.49 (d, 1H, H- , J 16.5 Hz); 6.85 (dd, 1H,
H-8, J 1.3 and 8.0 Hz); 7.01 (ddd, 1H, H-6, J 1.3, 7.6 and 8.0 Hz); 7.21 (ddd, 1H, H-7, J 1.3, 7.6 and 8.0 Hz);
7.57–7.62 (m, 5H, H-5, 20,60, 200,600); 7.75 (d, 1H, H- , J 16.5 Hz); 8.16 (d, 2H, H-30,50, J 8.8 Hz); 8.20
(d, 2H, H-300,500, J 8.8 Hz) ppm. 13C-NMR:
75.4 (C-2); 116.9 (C-8); 121.6 (C-4a); 122.5 (C-6); 123.9
(C-300,500); 124.2 (C-30,50); 125.5 (C-4); 125.8 (C-5); 127.1 (C- ); 127.2 (C-200,600); 128.6 (C-20,60); 129.1
(C-β); 130.6 (C-3); 131.6 (C-7); 142.6 (C-100); 144.3 (C-10); 147.2 (C-400); 148.1 (C-40); 152.0 (C-8a) ppm.
η 27%, m. p.
δ
β
α
δ
α

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3.6. General Procedure for the Synthesis of (Z- and E)-2-aryl-4-chloro-3-styrylquinoline-1(2H)-carbaldehydes
12a–i/13a–i
The appropriate phosphonium halide salt (8a
hydride (6 mg, 0.20 mmol) were placed in a previously dried flask. The mixture was heated at 60 ◦C
for 15, 7 and 3 min to prepare the ylide 9a 9b and 9c, respectively. After these periods, the formylated
derivative 2d was added (0.07 mmol). The reaction mixture was refluxed or maintained at room
–c, 0.20 mmol) in dry THF (20 mL) and sodium
,
–
f
temperature for the appropriate time depending of each formylated derivative (see Table 2). At the end,
the reaction mixture was poured into water (40 mL) and ice (50 g), the pH adjusted to 3 with dilute
hydrochloric acid. The reaction mixture was extracted with ethyl acetate (3
dried using anhydrous sodium sulphate and evaporated to dryness on the evaporator. The residue
×
20 mL), the solvent was
was purified by thin layer chromatography using mixtures of dichloromethane/hexane as eluent.
(E)-4-Chloro-2-phenyl-3-styrylquinoline-1(2H)-carbaldehyde (12a). Yellow solid,
m.p. 72–74 ◦C. 1H-NMR (300.13 MHz; CDCl3):
6.80 (d, 1H, H- , J 16.4 Hz); 6.97 (s, 1H, H-2); 7.02–7.05
(m, 1H, H-8); 7.20–7.35 (m, 10H, H-6,7, 30,40,50,200,300,400,500,600); 7.46 (m, 2H, H-20,60); 7.57 (d, 1H, H-
J 16.4 Hz); 7.81–7.84 (m, 1H, H-5); 8.68 (s, 1H, 1-NCHO) ppm. 13C-NMR (75.47 MHz; CDCl3):
52.2
(C-2); 118.2 (C-8); 123.1 (C-
); 126.0 (C-5); 126.2 (C-6); 126.5 (C-4a); 127.0 (C-4); 127.1 (C-20,60); 127.5
(C-200,600); 128.3 (C-40); 128.6 (C-400); 128.8 (C-30,50,300,500); 129.6 (C-7); 131.4 (C-10); 133.6 (C-
); 134.1
η 44% (11 mg),
δ
β
α
,
δ
β
α
(C-3); 136.5 (C-100); 137.2 (C-8a); 161.0 (1-NCHO) ppm. MS (ESI+) m/z (%): 394.1 35Cl [M + Na]+ (100),
396.1 37Cl [M + Na]+ (38). MS (ESI+) calcd for (C24H1835ClNO) 371.1077; found 371.1078. Calcd for
(C24H1837ClNO) 373.1047; found 372.1048.
(E)-4-Chloro-3-(4-nitrostyryl)-2-phenylquinoline-1(2H)-carbaldehyde (12c). Orange solid,
(12 mg), m.p. 243.5-245.3 ◦C. 1H-NMR (300.13 MHz; CDCl3):
6.81 (d, 1H, H- , J 16.4 Hz); 6.96 (s, 1H,
H-2); 7.04–7.07 (m, 1H, H-8); 7.23–7.32 (m, 7H, H-6,7, 20,30,40,50,60); 7.59 (d, 2H, H-20,60, J 8.8 Hz); 7.71 (d,
1H, H-
, J 16.4 Hz); 7.85–7.88 (m, 1H, H-5); 8.19 (d, 2H, H-300,500, J 8.8 Hz); 8.67 (s, 1H, 1-NCHO) ppm.
13C-NMR (75.47 MHz; CDCl3): 52.1 (C-2); 118.3 (C-8); 124.1 (C-300,500); 125.9 (C-4a); 126.2 (C-6); 126.7
(C-5); 127.2 (C-
); 127.3 (C-4); 127.4 (C-200,600, 20,60); 128.6 (C-40); 128.7 (C-30,50); 129.1 (C-3); 130.4 (C-7);
130.7 (C-
η 40%
δ
β
α
δ
β
α
); 134.3 (C-8a); 136.8 (C-10); 142.9 (C-100); 147.2 (C-400); 161.0 (1-NCHO) ppm. MS (ESI+) m/z
(%): 417.9 35Cl [M + H]+ (100), 419.9 37Cl [M + H]+ (3). MS (ESI+) calcd for (C24H1735ClN2O3) 416.0928;
found 416.0929. Calcd for (C24H1735ClN2O3) 418.0898; found 418.0100
(E)-4-Chloro-2-(4-methoxyphenyl)-3-styrylquinoline-1(2H)-carbaldehyde (12d). White solid,
η
46% (13 mg), m.p. 173–175 ◦C. 1H-NMR (300.13 MHz; CDCl3): 3.72 (s, 3H, 40-OCH3); 6.74 (d, 2H,
δ
H-30,50, J 8.8 Hz); 6.79 (d, 1H, H-
H-20,60, J 8.8 Hz); 7.22–7.28 (m, 3H, H-300,400,500); 7.33 (t, 2H, H-6,7, J 7.3 Hz); 7.45–7.48 (m, 2H, H-200,600);
7.54 (d, 1H, H-
, J 16.4 Hz); 7.80–7.84 (m, 1H, H-5); 8.67 (s, 1H, 1-NCHO) ppm. 13C-NMR (75.47 MHz;
CDCl3): ); 125.9 (C-6); 126.2 (C-5);
51.9 (C-2); 55.2 (40-OCH3); 114.1 (C-30,50); 118.2 (C-8); 123.0 (C-
126.5 (C-4a); 126.8 (C-4); 127.0 (C-300,500); 128.6 (C-400); 128.7 (C-20,60); 128.8 (C-200,600); 129.5 (C-10); 131.5
β, J 16.4 Hz); 6.91 (s, 1H, H-2); 7.01–7.04 (m, 1H, H-8); 7.21 (d, 2H,
α
δ
β
(C-3); 133.5 (C-α
); 134.0 (C-8a); 136.6 (C-100); 159.4 (C-40); 160.9 (1-NCHO) ppm. MS (ESI+) m/z (%):
424.1 35Cl [M + Na]+ (100); 426.1 37Cl [M + Na]+ (37). MS (ESI+) calcd for (C25H2135ClNO2) 402.1255;
found 402.1253. Calcd for (C25H2137ClNO2) 404.1255; found 402.1254.
(E)-4-Chloro-3-(4-ethoxystyryl)-2-(4-methoxyphenyl)quinoline-1(2H)-carbaldehyde (12e). Yellow
◦
η 27% (8 mg), m.p. 234–236 C. H-NMR (300.13 MHz; CDCl3):δ
1.41 (t, 3H, 400-OCH2CH3,
1
solid,
J 7,0 Hz); 3.70 (s, 3H, 40-OCH3); 4.04 (q, 2H, 400-OCH2CH3, J 7,0 Hz); 6.73 (d, 2H, H-300,500, J 8.8 Hz);
6.74 (d, 1H, H-
, J 16.2 Hz); 6.85 (d, 2H, H-30,50, J 8.8 Hz); 6.89 (s, 1H, H-2); 7.02–7.03 (m, 1H, H-8);
7.20 (d, 2H, H-20,60, J 8.8 Hz); 7.23–7.26 (m, 2H, H-6,7); 7.39 (d, 2H, H-200,600, J 8.8 Hz); 7.40 (d, 1H,
H-
, J 16.2 Hz); 7.79–7.82 (m, 1H, H-5); 8.66 (s, 1H, 1-NCHO) ppm. 13C-NMR (75.47 MHz; CDCl3):
14.8 (400-OCH2CH3); 51.8 (C-2); 55.1 (40-OCH3); 63.5 (400-OCH2CH3); 114.0 (C-300,500); 114.7 (C-30,50);
118.1 (C-8); 120.8 (C-
); 125.6 (C-100); 125.9 (C-5); 126.0 (C-6); 126.6 (C-4a); 128.4 (C-200,600); 128.8
(C-20,60); 129.2 (C-7); 129.5 (C-10) 131.9 (C-3); 133.2 (C- ,8a); 133.9 (C-4); 159.3 (C-40); 159.5 (C-400); 161.0
(1-NCHO) ppm. MS (ESI+) m/z (%): 445.9 35Cl [M + H]+ (100); 447.9 37Cl [M + H]+ (13).MS (ESI+)
β
α
δ
α
β

Molecules 2020, 25, 3791
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m/z calcd for (C27H2535ClNO3) 446.1516; found 446.1517. Calcd for (C27H2537ClNO3) 448.1516; found
446.1519.
(E)-4-Chloro-2-(4-methoxyphenyl)-3-(4-nitrostyryl)quinoline-1(2H)-carbaldehyde (12f). Yellow
solid,
H-30,50, J 8.7 Hz); 6.80 (d, 1H, H-
H-20,60, J 8.7 Hz); 7.29–7.32 (m, 2H, H-6,7); 7.58 (d, 2H, H-200,600, J 8.7 Hz); 7.69 (d, 1H, H-
7.84–7.88 (m, 1H, H-5); 8.18 (d, 2H, H-300,500, J 8.7 Hz); 8.67 (s, 1H, 1-NCHO) ppm. 13C-NMR (75.47 MHz;
CDCl3):
51.8 (C-2); 55.2 (C-40); 114.2 (C-30,50); 118.3 (C-8); 124.1 (C-300,500); 126.0 (C-4a); 126.1 (C-6);
126.6 (C-5); 127.2 (C-
); 127.4 (C-20,60); 128.7 (C-200,600); 128.9 (C-10); 129.6 (C-4); 130.4 (C-7); 130.6
(C-
η δ
53% (17 mg), m.p. 209–211 ◦C. 1H-NMR (300.13 MHz; CDCl3): 3.72 (40-OCH3); 6.76 (d, 2H,
β, J 16.1 Hz); 6.90 (s, 1H, H-2); 7.04–7.07 (m, 1H, H-8); 7.20 (d, 2H,
α
, J 16.1 Hz);
δ
β
α
); 130.8 (C-3); 134.3 (C-8a); 143.0 (C-100); 147.2 (C-400); 159.6 (C-40); 160.9 (1-NCHO) ppm. MS (ESI+)
m/z (%): 469.9 35Cl [M + Na]+ (100); 471.9 37Cl [M+Na]+ (2). MS (ESI+) calcd for (C25H2035ClN2O4)
447.1106; found 447.1110. Calcd for (C25H2037ClN2O4) 449.1106; found 448.1109.
(E)-4-Chloro-2-(4-nitrophenyl)-3-styrylquinoline-1(2H)-carbaldehyde (12g). Orange solid,
(9 mg), m.p. 179.9–180.7 ◦C. 1H-NMR (300.13 MHz; CDCl3):
6.74 (d, 1H, H- , J 16.4 Hz); 7.04 (s, 1H,
H-2); 7.04–7.07 (m, 1H, H-8); 7.29–7.38 (m, 5H, H-300,400,500,6,7); 7.46–7.49 (m, 4H, H-20,60, 200,600); 7.60
(d, 1H, H-
, J 16.4 Hz); 7.83–7.87 (m, 1H, H-5); 8.09 (d, 2H, H-30,50, J 8.8 Hz); 8.71 (s, 1H, 1-NCHO) ppm.
13C-NMR (75.47 MHz; CDCl3): ); 124.1 (C-30,50); 126.1 (C-4a); 126.5
51.3 (C-2); 118.2 (C-8); 122.8 (C-
(C-6); 126.54 (C-5); 127.1 (C-20,60); 127.7 (C-4); 128.6 (C-30,50); 128.9 (C-300,500); 129.0 (C-400); 130.0 (C-7);
η 30%
δ
β
α
δ
β
130.2 (C-8a); 133.5 (C-3); 133.7 (C-α
); 136.1 (C-10); 144.3 (C-10); 147.8 (C-40); 161.0 (1-NCHO) ppm. MS
(ESI+) m/z (%): 417.1 35Cl [M + H]+ (30); 419.1 37Cl [M + H]+ (2). MS (ESI+) calcd for (C24H1835ClN2O3)
417.0996; found 417.0999. Calcd for (C24H1837ClN2O3) 419.0996; found 417.0997.
(E)-4-Chloro-3-(4-ethoxystyryl)-2-(4-nitrophenyl)quinoline-1(2H)-carbaldehyde (12h). Yellow oil,
1
η
24%. H-NMR (300.13 MHz; CDCl3):
δ
1.42 (t, 3H, 400-OCH2CH3, J 7.0 Hz); 4.04 (q, 2H, 400-OCH2CH3,
J 7.0); 6.69 (d, 1H, H-
H-8); 7.27–7.31 (m, 2H, H-6,7); 7.40 (d, 2H, H-200,600, J 8.7 Hz); 7.47 (d, 2H, H-20,60, J 8.7 Hz); 7.47 (d,
1H, H-
, J 16.4 Hz); 7.81–7.84 (m, 1H, H-5); 8.08 (d, 2H, H-30,50, J 8.7 Hz); 8.70 (s, 1H, 1-NCHO) ppm.
13C-NMR (75.47 MHz; CDCl3): 14.8 (400-OCH2CH3); 51.3 (C-2); 63.6 (400-OCH2CH3); 114.8 (C-300,500);
118.2 (C-8); 120.5 (C-
); 124.1 (C-30,50); 126.2 (C-4a); 126.3 (C-5); 126.4 (C-6); 128.5 (C-200,600); 128.6
(C-20,60); 128.7 (C-100); 129.7 (C-7); 130.5 (C-3); 133.3 (C- ); 133.5 (C-4); 144.4 (C-10); 147.7 (C-40); 159.8
β
, J 16.4 Hz); 6.86 (d, 2H, H-300,500, J 8.7 Hz); 7.01 (s, 1H, H-2); 7.03–7.06 (m, 1H,
α
δ
α
β
(C-400); 161.1 (1-NCHO) ppm. MS (ESI+) m/z (%): 461.1 35Cl [M + H]+ (50); 463.1 37Cl [M + H]+ (3).MS
(ESI+) m/z calcd for (C26H2235ClN2O4) 461.1263; found 461.1261. Calcd for (C26H2237ClN2O4) 463.1263;
found 463.1263.
3.7. Theoretical Studies
Theoretic studies were performed get an insight into the selectivity of the Wittig reaction with
quinoline-3-carbaldehydes 2d
theory (DFT). Gaussian 09 et al. [33] was used for all single-point calculations employing the standard
fine grid and a B3LYP/6-31G(d) [34 36] level of theory. This is in agreement with the literature that
–f. All relevant structures were optimized using density functional
–
suggests that larger basis sets do not cause significant changes in the relative energies of the two
diastereomeric transition states, here in study. The use of THF as solvent was simulated using a
standard PCM model. Vibrational frequency calculations were performed to ensure the optimized
structures represented the local minima. All transition states here shown contained a single negative
frequency, and the corresponding eigenvector was verified to correspond to the expected reaction
coordinate. IRC calculations were also performed and lead to the formation of the next intermediate.
4. Conclusions
This work establishes that 2-aryl-4-chloro-2H-chromene-3-carbaldehydes are useful building blocks
and afforded several new derivatives in good yields. Interesting heterocycles, such as 3H-chromeno
quinolines, were obtained, and it also demonstrated that they could be used in Wittig reactions
to get new (Z and E)-2-aryl-4-chloro-3-styryl-2H-chromenes. It was evident that 2-aryl-4-chloro-

Molecules 2020, 25, 3791
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1,2-dihydroquinoline-1,3-dicarbaldehydes are less reactive. However, it was also possible to use
them in Wittig reactions, where they showed high selectivity towards the (E)-2-aryl-4-chloro-
3-styrylquinoline-1(2H)-carbaldehydes. This unique selectivity was explained through density functional
theory analysis.
Author Contributions: Investigation, D.H.A.R., E.J.F.B., V.F.B.; conceptualization, D.C.G.A.P. and A.M.S.S.;
supervision, D.C.G.A.P. and A.M.S.S.; validation, D.C.G.A.P. and A.M.S.S.; formal analysis, D.H.A.R., V.F.B.;
D.C.G.A.P. and A.M.S.S.; writing—original draft preparation, D.H.A.R., V.F.B.; D.C.G.A.P.; writing—review
and editing, D.C.G.A.P. and A.M.S.S. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: Thanks are due to the University of Aveiro and FCT/MCT for the financial support for
the QOPNA research Unit (UID/QUI/00062/2019) and the LAQV-REQUIMTE (UIDB/50006/2020) througH-National
funds and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to
the Portuguese NMR Network. D.H.A.R. and V.F.B. also thanks FCT for their PhD grant (SFRH/BD/68991/2010)
and (PD/BD/135099/2017), respectively.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).