An Appealing, Robust Access to Furo-Fused Heteropolycycles

Abstract

Recently, nitrostilbenes characterized by two different or differently substituted aryl moieties, obtainable from the initial ring-opening of 3-nitrobenzo[b]thiophene with amines, have proved, by means of a stepwise double coupling with phenolic-type bidentate C/O nucleophiles, to be valuable precursors of oxygen-containing heteropolycycles and of fully conjugated systems therefrom via an efficient 6π-electrocyclization and final aromatization. Herein, the methodology is extended, after suitable optimization, to diverse heterophenols to afford new appealing heteropolycyclic systems of potential interest as drug leads. The synthetic results are fully consistent with up-to-date quantomechanical calculations. For some of the new molecules, a significant fluorescence is reported, with a potential for future applications, e.g., in the field of optical devices.

1. Introduction

The recent literature witnesses an ever-growing number of publications concerning polycyclic systems characterized by the presence of one or more heteroatoms, testifying to the great interest of the scientific community in these compounds (Figure 1) [1]. Accordingly, new and/or more efficient synthetic approaches are desirable in order to further structurally and functionally diversify the final outcomes, including in the perspective of achieving new fields of application [2,3].

Among such an unbelievably wide class of compounds, aza-heterocycles are undoubtedly the most represented, often regarded as privileged structures [4,5]; they are also of outmost relevance from the biological/pharmacological point of view. However, many other rings are also raising great interest, and many other applicative fields can be cited, for instance, that of fluorescent compounds [6].

Within this field, we became interested in novel fused-heteropolycyclic structures, characterized by the presence of furan or dihydrofuran rings, as potential antioxidants imitating phenolic and polyphenolic natural compounds [7].

Recently, in our laboratory, the reaction of a series of stilbenes 1 with 2-naphthol A (Scheme 1, red) or, for a more limited series of substrates, with 8-hydroxyquinoline B (Scheme 1, blue) in K₂CO₃/DMSO turned out to be an effective access to fused dihydrofurans (DHF, 2) and furans (3), from which fully conjugated heteropolycyclic systems (4) could be generated by a 6π-electrocyclization followed by aromatization [8,9]. The final products exhibit interesting fluorescence properties, apart from potential pharmacological activity. An attempt to extend the reaction to 4-hydroxycoumarin C in the same experimental conditions met with failure, and the tentative use of different conditions (DABCO as an organic base in the less polar CHCl₃) was likewise unsatisfactory [8].

In order to improve the robustness and significance of our synthetic protocol, herein, we present results obtained under optimized experimental conditions from the reaction of nitrostilbenes 1a–e with 8-hydroxyquinoline (B) (thus extending the substrate scope) and with some structurally different O- or N-heteroaromatic bidentate (C/O) nucleophiles (C, D and E: Figure 2 where the expected initial coupling products are also sketched) (thus extending the nucleophile scope).

2. Results and Discussion

2.1. Reactions of Nitrostilbenes 1 with 8-Hydroxyquinoline (B)

2.1.1. Synthesis of Dihydrofurans 2B

Our first target was to extend the range of stilbenes generating dihydrofurans from 8-hydroxyquinoline B (Scheme 2) and, thus, increase the substrate scope of our double-coupling methodology.

Table 1. Results obtained in the reactions of 1a–e with 8-hydroxyquinoline in the presence of K₂CO₃ (1.2 equiv.), in DMSO at room T (Scheme 3).

Ar in 1		t	Yields in 2Ba–e	t a	Yields in 2Ba–c a
p-Tolyl	a	24 h	70%	4 h	90%
p-MeO-Phenyl	b	24 h	66%	4 h	58%
p-Cl-Phenyl	c	24 h	74%	4 h	81%
1-Naphthyl	d	45 h	30%
2-Thienyl	e	24 h	40%

^a Data from ref. [8].

collects the data obtained under the same conditions utilized with 2-naphthol A [8], i.e., 1 mol equiv. of B and 1.2 equiv. of K₂CO₃, in DMSO.

The initial formation of the dihydrofuroquinolines rests on a sequential double coupling between the twofold (C/C) electrophilic nitrostilbene and the twofold (O/C) nucleophilic phenolic derivative, as sketched in Scheme 3.

The proposed mechanism features an initial Michael-type coupling whereby the bidentate anion generated by deprotonation of the phenolic group behaves as a C-nucleophile toward the nitrovinyl moiety of 1. Re-aromatization of the phenolic ring with intramolecular displacement of the nitro group, most likely assisted by protonation, completes the dihydrofuran ring formation, a mechanism that received definite support in our previous work by the X-ray structural determination of the dihydrofuro-fused derivative 2Aa of Scheme 1 [8].

The same mechanism most likely holds for all the bidentate nucleophiles tested herein. Thus, as a further sample test, the structure of the furan-fused coumarin 3Ca has been, in turn, confirmed by an X-ray analysis; the ORTEP reported in Figure 3 also shows the presence of a molecule of the solvent (ethanol) used for the crystallization.

As a matter of fact, C-C couplings of phenols or condensed phenols with electrophiles, such as typical Michael acceptors [10,11,12] as well as carbonyls [13] or nitroalkenes [14] (also envisaged as Friedel–Crafts aromatic substitutions), in some cases eventually leading to fused dihydrofurans [13,14], are well documented in the literature, both in basic [10,11] and in acidic conditions [12,13,14].

As shown by the data in Table 1, the reactions with 1d and 1e proved to be very slow, further leading to rather poor final yields. For the sake of completeness and in order to verify the stability of dihydrofurans with time, the reactions on 1a–c were prolonged to 24 h (fourth column): the comparison with our previous data [8] (last column) did not unveil major differences in yields with time but some significant decrease for 2Ba.

The rather unsatisfactory outcomes with 1d and 1e remain somehow surprising in the light of the efficient coupling of such nitrostilbenes experienced with 2-naphthol [8]: at the moment though, no sounding explanation can be provided (regarding 1e, see hereinafter about the coupling with C: Section 2.2.1).

2.1.2. Aromatization of the Dihydrofuroquinolines 2B to 3B

The dihydrofurans 2Ba–e were subjected to the oxidative conditions already used for naphthofurans [8] (Scheme 4), observing good to excellent yields of the desired aromatized 3Ba–e (

Table 2. Oxidative aromatization of 2Ba–e to furoquinolines 3Ba–e with DDQ (2 mol equiv.) in CHCl₃ (Scheme 4).

Ar in 2B		t	T	Yields in 3Ba–e
p-Tolyl	a	24 h	r.t.	91%
p-MeO-Phenyl	b	24 h	r.t.	90%
p-Cl-Phenyl	c	27 h	r.t.	73%
1-Naphthyl	d	30 h	60 °C	85%
2-Thienyl	e	24 h	r.t.	99%

). The reaction of the naphthyl derivative was too slow at r.t. requiring a higher temperature.

2.2. Reactions of Nitrostilbenes 1 with 4-Hydroxycoumarin (C)

2.2.1. Synthesis of Dihydrofurans 2C

The double-coupling protocol was extended to 4-hydroxycoumarin (C), preceded by a literature search for suitable reaction conditions: this is because, as already recalled above, the reaction with the model nitrostilbene 1a under the usual conditions (K₂CO₃/DMSO) failed to produce significant amounts of 2Ca, while the DABCO/CHCl₃ system led to a very poor yield (13%) [8]. On the other hand, the hydroxycoumarin moiety represents, in particular, a very promising privileged structure as it characterizes the biological activity of both natural and synthetic molecules [15,16,17,18,19,20], thus justifying further synthetic efforts aimed at functional and/or structural/geometrical diversification.

Quite rewardingly, far better results were obtained when employing triethylamine (2 mol equiv.) at 60 °C in CHCl₃ (Scheme 5 and

Table 3. Results obtained in the reactions of 1a–e with 4-hydroxycoumarin, in Et₃N/CHCl₃ at 60 °C for 24 h.

Ar in 1		Yields in 2Ca–e
p-Tolyl	a	79%
p-MeO-Phenyl	b	68%
p-Cl-Phenyl	c	83%
1-Naphthyl	d	76%
2-Thienyl	e	10% a

^a A different reaction took over: see the text below.

). Surprisingly enough, in these conditions, 1d (Ar = 1-naphthyl) lined up with 1a–c, as observed with 2-naphthol A [8].

On the other hand, with the 2-thienyl derivative 1e, only minor amounts of the expected 2Ce could be isolated. The presence, in the final reaction mixture (79%), of the nitrosulfone 4 (Scheme 6) could suggest the occurrence of a fragmentation of the nitrostilbene via a retro-Henry process [21,22] (Scheme 6, path A), sometimes observed in our laboratories in nitrobutadienes under basic conditions. Nonetheless, a control reaction on 1e with Et₃N in CHCl₃ left the stilbene unchanged, so testifying that a retro-Henry cannot be responsible for the formation of 4.

Another hypothesis was then considered whereby the main isolated product would derive from an initially formed Michael adduct I′ (Scheme 6, path B) and then evolve along two competitive pathways. It should be noticed that from the chromatographic column, only 2Ce and 4 were isolated, indicating the presence of some non-eluted, very polar, colored products.

To overcome the negative outcome above, a different set of experimental conditions was tested, namely, DABCO in EtOH at reflux [23], which, at last, allowed to isolate compound 2Ce in a satisfactory 74% yield (

Table 4. Results in reactions of 1c–e with 4-hydroxycoumarin in DABCO/EtOH at reflux.

Ar in 1		t	Yields in 2Ce,c,d
2-Thienyl	e	16 h	74%
p-Cl-Phenyl	c	4 h	70%
1-Naphthyl	d	24 h	76%

). These conditions proved to be more advantageous from the practical point of view as the product precipitates and can be isolated as a pure white solid by filtration: accordingly, for the sake of comparison, the same conditions were also tested with substrates 1c,d, with overall satisfactory results.

2.2.2. Aromatization of the Dihydrofurocoumarins 2C to 3C

The aromatization of 2C to 3C with DDQ (Scheme 7) required some optimization of the experimental conditions. With the model substrate 2Ca, the best results were obtained by raising the number of DDQ molar equivalents (4), temperature (60 °C), and time (5 days) (

Table 5. Search for the best conditions for the aromatization of 2Ca to furocoumarin 3Ca with DDQ.

Solvent	DDQ mol equiv.	T	t	Yields in 3Ca
CHCl3	2	r.t.	24 h	14%
CHCl3	3	60 °C	48 h	40%
Toluene	8	110 °C	28 h	12%
CHCl3	4	60 °C	5 days	90%

). The use of toluene as solvent, which would allow for higher temperatures, gave a far poorer result.

The conditions optimized for 2Ca were then extended to the other substrates (

Table 6. Oxidative aromatization of 2Ca–e to furocoumarins 3Ca–e with DDQ (4 mol equiv.) in CHCl₃ at 60 °C.

Ar in 2C		t	Yields in 3Ca–e
p-Tolyl	a	96 h	99%
p-MeO-Phenyl	b	48 h	99%
p-Cl-Phenyl	c	11 days	42% a
1-Naphthyl	d	28 h	0%
2-Thienyl	e	24 h	99%

^a Not isolated. Yields evaluated by ¹HNMR analysis of chromatographically isolated mixtures with 2Cc.

), but while 2Cb and 2Ce (electron-rich substrates) were easily oxidized, the two remaining DHFs either reacted very slowly (2Cc) or did not react at all (2Cd).

As to the former outcome, it should be kept in mind that the presence of the electron-withdrawing p-Cl substituent would make the substrate electron-poor and, thus, reluctant to oxidation. Please note that an evaluation of the conversion was possible only by ¹H NMR analysis because any attempt of chromatographic separation failed: 2Cc and 3Cc had the same Rf with all the eluents tested. Furthermore, the fluorescence of 3Cc hid the spot of 2Cc.

As to the complete failure of the naphthyl derivative 2Cd to undergo oxidation, it should be stressed that none of many other oxidants tested for its aromatization met with success: I₂ and DBU in DCM at rt, 24 h [24]; MnO₂ in DCM at 40 °C, 24 h [25]; PIDA/AcOH, 110 °C, 48 h [26,27]; TEMPO/FeCl₃/NaNO₂/O₂/MeCN/rt/3 h [28].

A tentative qualitative explanation for such a failure could refer to a difficulty of 3Cd to reach coplanarity of all of its aromatic rings, thus gaining little or no stabilization from an extended conjugation. Anyway, under such a perspective, the result remains very disappointing and somehow unexpected when compared to the results for the corresponding naphthofuran (2Ad) [8] and furoquinoline 2Bd (Scheme 8).

To gain insight into this outcome, we conducted comparative quantomechanical calculations on 2Cd and the easily oxidized 2Ad and 2Bd in order to envisage any stereoelectronic feature possibly related to the observed differences in reactivity.

First, a conformational search procedure was performed on their models (DFT:B3LYP/6-31G*//DFT:B97M-V/6-311+G(2df,2p)[6-311G*]), obtaining all possible local minimum conformations within a 5 kcal/mol window above the global minimum. The conformational space of 2Ad is more populated (five conformers), while those of 2Bd and 2Cd are equally populated (2 conformers).

Subsequently, we calculated the HOMO density map over the sigma bond skeleton (DFT:ωB97X-V/6-311+G**//DFT:ωB97X-V/6-311+G(2df,2p)[6-311G*]) for the most stable conformers of 2Ad, 2Bd and 2Cd (Figure 4). The HOMO is uniformly spread over the tricyclic plane of naphthofuran in 2Ad and furoquinoline in 2Bd, while in the furocoumarin 2Cd, the largest contribution to the HOMO comes from the naphthalene moiety, with minimal contribution from the tricyclic system. Consequently, for the latter, electron movement can hardly occur in the region where aromatization is aimed.

This peculiar HOMO distribution appears to be the primary factor hampering the aromatization of 2Cd, while hindering steric factors (suggested by the reduced conformational space) might create obstacles in the spatial arrangement of the substituents both in 2Cd and 2Bd, preventing optimal conjugation and limiting the effectiveness of aromatization of the furan ring, thus contributing to the unsuccessful aromatization of 2Cd and reducing the aromatization yield of 2Bd.

Encouraged by these intriguing results, we extended the same calculations to 2Ca, 2Cb, 2Cc, and 2C in order to determine whether a similar rationale could also explain the reactivity of the other 2C compounds (as shown in Table 6), in particular, the relatively modest aromatization tendency of the p-Cl-phenyl-derivative 2Cc compared to the much higher efficiency of the process on its congeners.

The conformational space of 2Cc (2 conformers within a 5 kcal/mol window above the global minimum) is less populated than those of 2Ca (5 conformers), 2Cb (4 conformers), and 2Ce (4 conformers), and equally populated as that of 2Cd. This suggests that hindering steric factors may play a role in the less efficient aromatization of 2Cc.

Additionally, the HOMO density map for all these compounds spreads over both the tricyclic furocoumarin system and the 3-aryl moiety (though not uniformly); interestingly enough, only in the case of 2Cc, it does not interest the region of the [4,5]-furan bond (Figure 5 (last row)), which is the actual site of the aimed aromatization.

Thus, both steric and electronic factors likely contribute to explaining the experimental outcomes for the aromatization of 2C to 3C.

2.3. Extension of the Coupling Methodology with Nitrostilbenes 1 to Other Heterocyclic Phenols: 5-Hydroxyindole (D) and N,N′-Dimethylbarbituric Acid (E)

On the grounds of the rewarding results obtained with A, B, and C, the coupling reaction with nitrostilbenes 1 was applied to other phenols in order to build up new heteropolycyclic systems, especially those containing nitrogen atoms.

2.3.1. Synthesis of Dihydrofurans 2D and of the Relevant Aromatized Furans 3D

Conditions and results of the coupling reaction between 1a–e and D are reported in

Table 7. Results obtained in the reactions of 1a–e with 5-hydroxyindole in CH₃CN/H₂O 97/3 at 60 °C, followed by complete aromatization of DHFs 2D in DDQ/toluene at r.t. for 10 min. (see Scheme 9).

		CH3CN/H2O 97/3, 60 °C					DDQ/Tol, r.t. 10 min
Ar in 1		t	2D	3D	Ar in 2D		3D
p-Tolyl	a	16 h	76%	12%	p-Tolyl	a	93%
p-MeO-Phenyl	b	40 h	66%	12%	p-MeO-Phenyl	b	99%
p-Cl-Phenyl	c	5 h	44%	20%	p-Cl-Phenyl	c	98%
1-Naphthyl	d	48 h	60%	10%	1-Naphthyl	d	97%
2-Thienyl	e	52 h	61%	16%	2-Thienyl	e	99%

. Surprisingly enough, the expected dihydrofurans were always isolated in a mixture with minor quantities of the corresponding aromatized furan derivatives. The aromatization was easily completed by oxidation with DDQ (Table 7 and Scheme 9).

2.3.2. Synthesis of Dihydrofurans 2E and of the Relevant Aromatized Furans 3E

Conditions and results of the coupling reaction between 1a–d and E are reported in

Table 8. Results obtained in the reactions of 1a–e with N,N′-dimethylbarbituric acid in CH₃CN/H₂O 97/3 at 60 °C for 24 h and of the following aromatization of the representative 2Eb in DDQ/CHCl₃ at 60 °C (see Scheme 10).

		CH3CN/H2O 97/3, 60 °C, 24 h			DDQ/CHCl3, 60 °C, 29 h
Ar in 1		2E	Ar in 2E		3E
p-Tolyl	a	68%
p-MeO-Phenyl	b	48%	p-MeO-Phenyl	b	99%
p-Cl-Phenyl	c	71%
1-Naphthyl	d	88%
2-Thienyl	e	46% *

* Not isolated. Yields evaluated by ¹HNMR analysis of chromatographically isolated mixtures with an unknown product.

.

The aromatization to furan derivatives 3E has been accomplished on model 2Eb in order to verify the feasibility of the oxidative step.

2.4. 6π-Electrocyclization, Followed by Aromatization, of Furoquinolines 3Ba–e and Furocoumarins 3Ca,b,e

Driven by the ever-growing interest of researchers in fluorescence, e.g., for the OLED technology [29], and encouraged by the fluorescence already displayed by both DHFs (2Ba) and furans (3Ba) in the quinoline series [8], we aimed to build up more extended systems of fully conjugated π-electrons, which would, hopefully, increase fluorescence properties through a 6π-electrocyclization followed by complete aromatization of the condensed furan derivatives described in the previous paragraphs, by applying the methodology proven quite satisfactory for naphtho-fused analogs [8], viz. photostimulation in acetone.

Initially, acetone solutions of 3Ba–c were sealed in a quartz tube and placed in a Rayonet photochemical reactor equipped with 300 nm lamps. Not surprisingly, we never observed the cyclohexadienes expected from the electrocyclization process, which, instead, proceeded to aromatization to 5Ba–c thanks to an easy elimination, under the same conditions, of methanesulfinic acid from E1 after a 1,5-H-shift to E2 (

Table 9. 6π-Electrocyclization, followed by aromatization, of 3Ba–e to compounds 5Ba–e in acetone in a Rayonet photochemical reactor.

Ar in 3B		hν	t	5B	hν a	t a	5B
p-Tolyl	a	300	24 h	52%	350	16 h	70%
p-MeO-Phenyl	b	300	24 h	29%	350	16 h	73%
p-Cl-Phenyl	c	300	24 h	57%	350	17 h	62%
1-Naphthtyl	d	300	24 h		350	24 h	68%
2-Thyenyl	e	300	24 h		350	16 h	50%

^a In the presence of 1 mol equiv. of DBU.

and Scheme 11 exemplify the process on 3Ba). On steric grounds, we disfavor the electrocyclization to E3.

We observed, however, generally rather modest yields (Table 9, column 5), especially for the electron-rich 3Bb, possibly due to the partial decomposition of the products by the heat developed. A successful attempt to improve the yields was the use of less energetic radiation (increasing the wavelength λ from 300 to 350 nm). Moreover, we hypothesized that the introduction of a base (DBU) in the system could make the acid elimination faster, thus exposing the products for a shorter time to potentially degrading conditions. Actually, the addition of 1 mol equiv. of DBU made the reactions faster and yields higher (Table 9, columns 7 and 8).

The modified conditions were then applied to substrates 3C to obtain 5C again in satisfactory yields (

Table 10. The 6π-electrocyclization reaction of 3Ca,b,e followed by oxidative aromatizatio to generate compounds 5Ca,b,e (acetone solution, 1 mol equiv. of DBU, irradiation at 350 nm for 16 h).

Ar in 3C		5C
p-Tolyl	a	70%
p-MeO-Phenyl	b	73%
2-Thienyl	e	65% a

^a We could only assume that the yield refers to the expected product because the reaction proceeded similarly to the other terms: unfortunately, any attempt to characterize the product failed due to its insolubility in any solvent tested.

). From the practical point of view, it is noteworthy that the product 5C precipitated completely in the reaction solvent, greatly simplifying the work-up; as far as obtaining a pure solid, it was sufficient to wash the precipitate with cold acetone until the solvent became colorless.

2.5. Fluorescence Analysis

One goal of the present protocol was to generate molecules endowed with significant fluorescence properties: as already recalled, for quinoline derivatives fluorescence appears in DHF, furans, and electrocyclized products; for coumarins, instead, only furans and electrocyclized derivatives are fluorescent [30], probably thanks to more extended fully conjugated systems.

A qualitative visualization of fluorescence under UV irradiation is shown in Figure 6. Quantitatively, the most important fluorescence parameters are the Stokes shift and the quantum yield, calculated as described in the following Equations (1) and (2), respectively [31].

$$\Delta \overline{\nu }={\overline{\nu }}_{ab}-{\overline{\nu }}_{em}={\displaystyle \frac{{10}^7}{{\lambda }_{{max}_{ab}}}}-{\displaystyle \frac{{10}^7}{{\lambda }_{{max}_{em}}}}$$

(1)

Equation (1). The formula used to determine the Stokes shift ($\Delta \overline{\nu }$) where ${\overline{\nu }}_{ab}, {\overline{\nu }}_{em}$ and ${\lambda }_{{max}_{ab}}$, ${\lambda }_{{max}_{em}}$ represent, respectively, the wave numbers (in nm) and the wavelengths (in cm⁻¹) of the maximum absorption and emission.

$${\varphi }_X={\varphi }_R {\displaystyle \frac{1-{10}^{-A_R}}{1-{10}^{-A_X}}} {\displaystyle \frac{S_X}{S_R}} {\displaystyle \frac{{\mu }_X^2}{{\mu }_R^2}}$$

(2)

Equation (2). The formula used to calculate the Quantum Yield (Φ) where A represents the absorbance at the wavelength of excitation, S is the area of the surface subtended in the spectrum along the interval of the λ_em, and μ is the solvent refraction index; “X” refers to the analyzed sample, and “R” refers to the standard.

Table 11. Fluorescence data for quinoline derivatives 2Bb, 3Bb–e and 5Ba–e; and for coumarin derivatives 3Ca,b,e and 5Ca,b.

Compound	λmax (ab) [nm]	λmax (em) [nm]	$\Delta \overline{\mathit{\nu }}$ [cm−1]	$\mathit{\varphi }$
2Bb	330	411	5972	0.037
3Bb	329	433	7300	0.160
3Bc	324	396	5612	0.200
3Bd	297	407	9100	0.410
3Be	325	434	7728	0.151
5Ba	327	420	6772	0.694
5Bb	328	442	7863	0.459
5Bc	326	407	6105	0.258
5Bd	305	407	8217	0.712
5Be	290	423	10,842	0.478
3Ca	334	405	5249	0.206
3Cb	341	438	6494	0.109
3Ce	332	442	7496	0.126
5Ca	364	412	3201	0.427
5Cb	371	441	4278	0.329

collects the data of the compounds analyzed, allowing some comparative considerations among quinoline (green) and coumarin (blue) derivatives.

With regard to the quinoline derivatives, the higher quantum yields are shown, as expected, by the electrocyclized and fully aromatized 5B compounds, which were prepared on purpose to obtain a more rigid planar system and extended conjugation; among them, the best performer is the 1-naphthyl-derivative 5Bd due to the presence of the 1-naphthyl ring (as confirmed by the fact that the corresponding 1-naphthyl-substituted 3Bd is the furoquinoline with the highest quantum yield).

Considering coumarin derivatives, they show generally lower quantum yields, which are rather good for the electrocyclized 5Ca,e; unluckily, the 5Cd naphthyl-derivative (which would probably show the highest quantum yield of the series) could not be obtained (as previously discussed).

3. Experimental Section

3.1. Materials and Methods

¹H NMR and ¹³C NMR spectra were recorded with a JEOL JNM-ECZR 400 spectrometer (Akishima, Japan) at 400 and 100 MHz, respectively; chemical shifts (TMS as internal reference) are reported as δ values (ppm). Signals are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; t, triplet; tt, triplet of triplets; m, multiplet; br, broad. High-resolution mass spectra (HRMS) were obtained with an Agilent MSD TOF mass spectrometer (Santa Clara, CA, USA) and recorded in positive ion mode with an electrospray (ESI) source. Melting points were determined with a Büchi 535 apparatus (Uster, Switzerland) and are uncorrected. Petroleum ether and light petroleum refer to the fractions with bp 40–60 °C and 80–100 °C, respectively. Silica gel 230–400 mesh or neutral aluminum oxide Acros Organics (Geel, Belgium, 50–200 μm), were used for column chromatography. TLC analyses were performed on commercially prepared 60 F254 silica gel plates (VWR, Radnor, PA, USA) and visualized by UV irradiation (eluant: petroleum ether—ethyl acetate). All commercially available reagents were used as received.

As already reported [32,33], the substrates employed (1a–e) were obtained starting from 3-nitrobenzo-thiophene, herein prepared in higher yields according to a literature procedure [34,35], different from the one usually employed [36,37].

Absorption spectra were recorded using a Perkin Elmer Lambda9 UV/VIS/NIR Spectrophotometer (Waltham, MA, USA), while fluorescence spectra were recorded (at the excitation wavelengths of 254 nm and 440 nm) with the Perkin Elmer MPF-44A Fluorescence Spectrophotometer and were normalized using Rhodamine B in PMMA as the reference standard. Compounds were analyzed as 100 µmol ethanolic solutions. Calculations were made with software the “LabPlot” (v. 2) software.

3.2. Quantum Mechanical Calculations

The models for compounds 2Ad, 2Bd, 2Ca, 2Cb, 2Cc, 2Cd, and 2Ce were generated from atomic fragments incorporated into the internal fragment library of the computational software Spartan’24 (v. 1.2.0, Wavefunction Inc. Irvine, CA, USA) starting from the suggested geometries [38] These models were optimized using the systematic/MonteCarlo method with the MMFF94 force field.

A systematic conformational distribution analysis was then performed, following the steps below:

(1)

Up to 200 conformers within a 40 Kcal/mol energy window above the global minimum conformer were initially selected for further geometry optimization in the gas phase using ab initio Hartree–Fock calculations at the 3-21G level.

(2)

Up to 100 conformers in a 20 Kcal/mol energy window were selected and further optimized using density-functional theory (DFT) implemented with ωB97X-D density functional and 6-31G* basis set.

(3)

Up to 50 conformers in a 10 Kcal/mol energy window were selected and further refined by DFT calculations with the ωB97X-V functional and the 6-311+G(2df,2p)[6-311G*] basis set.

(4)

Up to 25 conformers in a 5 Kcal/mol window were selected and their optimized structures were confirmed as real minima by IR frequency calculation (no imaginary frequencies).

The HOMO density distributions were calculated at the DFT ωB97X-V/6-311+G(2df,2p)[6-311G*] level on the DFT:ωB97X-V/6-311+G** most stable conformers (i.e., global minimum conformers) of each compound.

The HOMO density distributions were also calculated (in the same way) for the second most stable conformer of each compound and confronted with that of the most stable one, showing no relevant differences.

3.3. General Procedure for the Reactions of Substrates 1a–e with 8-Hydroxyquinoline B

The procedure was already reported in a previous paper [8] and has been herein extended to substrates 1d and 1e. In addition, here reaction times were prolonged, allowing for obtaining better yields.

In a flask, the relevant nitrostilbene 1 (0.15 mmol) was dissolved in DMSO (1 mL), and 8-hydroxyquinoline (0.15 mmol) and K₂CO₃ (0.19 mmol) were added as solids under magnetic stirring. The reaction was stirred at room temperature and monitored by TLC. Upon completion (24–45 h), the mixture was diluted with 20 mL of ethyl acetate, washed with HCl 1M (2 × 5 mL), NaHCO₃ (2 × 5 mL), water (1 × 5 mL), and brine (1 × 5 mL). The organic phase was dried with anhydrous Na₂SO₄, and, after filtration, the solvent was evaporated. The crude was purified by column chromatography (petroleum ether/ethyl acetate 1:1 to 1:2), obtaining compounds 2Ba–e. Hereinafter, we report the characterization of the two newly obtained dihydrofuroquinolines.

• 2-(2-(Methylsulfonyl)phenyl)-3-(1-naphthyl)-2,3-dihydrofuro[3,2-h]quinoline (2Bd). White solid. M.p. 151.0–152.7 °C (taken-up with E.P/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 8.91 (dd, J = 4.5, 1.7 Hz, 1H), 8.19 (dd, J = 8.4, 1.7 Hz, 1H), 8.10 (dd, J = 7.7, 1.7 Hz, 1H), 7.86 (dd, J = 8.3, 1.3 Hz, 1H), 7.83–7.76 (m, 1H), 7.68 (s, 1H), 7.65–7.50 (m, 4H), 7.50–7.37 (m, 5H), 7.32–7.19 (m, 1H), 6.78 (br s, 1H), 6.03 (br s, 1H), 2.87 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 150.22, 140.38, 138.84, 138.04, 136.34, 136.03, 134.28, 133.85, 132.36, 131.93, 130.19, 129.55, 129.43, 129.02, 128.14, 126.35, 125.93, 125.66, 123.72, 122.74, 121.53, 121.38, 90.16, 53.53, 45.52 (three signals not visible because of isochrony). HRMS (ESI) m/z calculated [M + H]⁺ C₂₈H₂₂NO₃S⁺ 452.1242, found 452.1244.
• 2-(2-(Methylsulfonyl)phenyl)-3-(2-thienyl)-2,3-dihydrofuro[3,2-h]quinoline (2Be). White solid. M.p. 174.0–175.6 °C (taken-up with E.P/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.20 (dd, J = 8.4, 1.7 Hz, 1H), 8.16 (dt, J = 7.6, 1.1 Hz, 1H), 7.62–7.58 (m, 2H), 7.54 (ddd, J = 7.6, 5.4, 3.5 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.44 (dd, J = 8.4, 4.2 Hz, 1H), 7.35 (dd, J = 8.2, 0.8 Hz, 1H), 7.25 (dd, J = 5.1, 1.3 Hz, 1H), 6.98 (dd, J = 5.1, 3.5 Hz, 1H), 6.95 (dd, J = 3.7, 1.3 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.38 (d, J = 8.1 Hz, 1H), 3.14 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 154.33, 150.25, 144.22, 139.54, 138.94, 136.35, 135.91, 134.16, 130.32, 129.73, 129.51, 129.47, 127.51, 127.24, 126.27, 125.30, 123.50, 121.65, 121.42, 90.23, 53.94, 45.78. HRMS (ESI) m/z calculated [M + H]⁺ C₂₂H₁₈NO₃S₂⁺ 408.0650, found 408.0658.

3.4. General Procedure for the Reactions of Substrates 1a–e with 4-Hydroxycoumarin C

In a round-bottom flask, the substrate 1 (0.157 mmol) was dissolved in chloroform (1.5 mL); then, 4-hydroxycoumarin (0.32 mmol) and Et₃N (0.32 mmol) were added. The reaction was stirred at 60 °C for 24 h. The crude was purified by column chromatography (petroleum ether/ethyl acetate 2:1, then 1:1 and 1:2). These conditions represent a definite improvement with respect to the first attempt on the model substrate 1a reported in [8] where an unsatisfactory (37%) yield was obtained. However, they failed when applied to substrate 1e (Ar = 2-Th).

• 2-(2-(Methylsulfonyl)phenyl)-3-(p-tolyl)-2,3-dihydro-4H-furo[3,2-c]chromen-4-one (2Ca). White solid. M.p. 219.9–220.8 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.12 (dd, J = 8.0, 1.4 Hz, 1H), 7.75 (dd, J = 7.8, 1.7 Hz, 1H), 7.71 (td, J = 7.5, 1.4 Hz, 1H), 7.67–7.57 (m, 3H), 7.42 (dd, J = 8.5, 1.0 Hz, 1H), 7.33 (td, J = 7.6, 1.1 Hz, 1H), 7.20–7.10 (m, 4H), 6.98 (d, J = 6.4 Hz, 1H), 4.65 (d, J = 6.4 Hz, 1H), 2.73 (s, 3H), 2.30 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 166.11, 159.53, 155.57, 138.94, 138.48, 137.93, 136.44, 134.83, 133.09, 130.04, 129.97, 129.90, 128.52, 127.63, 124.29, 123.23, 117.26, 112.28, 105.67, 90.12, 55.37, 45.57, 21.28. HRMS (ESI) m/z calculated [M + H]⁺ C₂₅H₂₁O₅S⁺ 433.1031, found 433.1027.
• 3-(4-Methoxyphenyl)-2-(2-(methylsulfonyl)phenyl)-2,3-dihydro-4H-furo[3,2-c]chromen-4-one (2Cb). White solid. M.p. 214.9–216.1 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.12 (dd, J = 7.9, 1.4 Hz, 1H), 7.75 (dd, J = 7.8, 1.6 Hz, 1H), 7.71 (td, J = 7.6, 1.4 Hz, 1H), 7.65–7.56 (m, 3H), 7.42 (dd, J = 8.5, 1.1 Hz, 1H), 7.33 (td, J = 7.6, 1.1 Hz, 1H), 7.25–7.16 (m, 2H), 6.97 (d, J = 6.4 Hz, 1H), 6.90–6.82 (m, 2H), 4.65 (d, J = 6.4 Hz, 1H), 3.77 (s, 3H), 2.76 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 166.01, 159.52, 159.43, 155.58, 138.96, 138.52, 134.80, 133.06, 131.47, 130.02, 129.90, 128.86, 128.49, 124.27, 123.21, 117.26, 114.64, 112.29, 105.70, 90.10, 55.35, 55.01, 45.60. HRMS (ESI) m/z calculated [M + H]⁺ C₂₅H₂₁O₆S⁺ 449.0981, found 449.0990.
• 3-(4-Chlorophenyl)-2-(2-(methylsulfonyl)phenyl)-2,3-dihydro-4H-furo[3,2-c]chromen-4-one (2Cc). White solid. M.p. 253.0–253.7 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.13 (dd, J = 7.9, 1.4 Hz, 1H), 7.75 (dd, J = 7.8, 1.6 Hz, 1H), 7.70 (td, J = 7.6, 1.5 Hz, 1H), 767–7.60 (m, 2H), 7.60–7.55 (m, 1H), 7.44 (dd, J = 8.5, 1.0 Hz, 1H), 7.35 (dd, J = 7.6, 1.1 Hz, 1H), 7.34–7.28 (m, 2H), 7.26–7.19 (m, 2H), 6.94 (d, J = 5.9 Hz, 1H), 4.65 (d, J = 5.8 Hz, 1H), 2.88 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 166.23, 159.37, 155.62, 138.57, 138.33, 138.14, 134.85, 134.01, 133.31, 130.20, 130.07, 129.36 129.10, 128.16, 124.40, 123.18, 117.37, 112.10, 105.43, 89.92, 54.91, 45.65. HRMS (ESI) m/z calculated [M + H]⁺ C₂₄H₁₈ClO₅S⁺ 453.0485, found 453.0492.
• 2-(2-(Methylsulfonyl)phenyl)-3-(1-naphthyl)-2,3-dihydro-4H-furo[3,2-c]chromen-4-one (2Cd). White solid. M.p. 216.0–217.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.11 (dd, J = 8.1, 1.4 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.87–7.78 (m, 3H), 7.76 (dd, J = 7.8, 1.6 Hz, 1H), 7.70–7.61 (m, 2H), 7.54–7.43 (m, 4H), 7.40 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 7.34 (td, J = 7.6, 1.1 Hz, 1H), 7.26–7.23 (m, 1H), 6.89 (br s, 1H), 5.69 (br s, 1H), 2.29 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 166.98, 159.53, 155.70, 139.17, 138.87, 135.08, 134.20, 133.24, 131.46, 130.41, 130.11, 129.30, 128.90, 128.80, 126.54, 126.08, 126.00, 124.33, 123.30, 122.65, 117.29, 112.35, 104.60, 100.02, 90.28, 45.02 (two isochronous carbon). HRMS (ESI) m/z calculated [M + H]⁺ C₂₈H₂₁O₅S⁺ 469.1031, found 469.1023.

3.5. Alternative Procedure for the Reaction of Substrates 1c–e with 4-Hydroxycoumarin C

In a round-bottom flask, the substrate 1e (0.157 mmol) was dissolved in ethanol (1.5 mL); then, 4-hydroxycoumarin (0.32 mmol) and DABCO (0.24 mmol) were added. The reaction mixture was heated to 85 °C under magnetic stirring until the substrate disappeared (TLC). The product (a white solid) precipitated in EtOH, so it could be separated by filtration and washed with ethanol. The resulting products were pure enough and chromatography was not necessary. These conditions were also applied to the substrate 1c and 1d, confirming the solidity of the method and the easier isolation of the product.

• 2-(2-(Methylsulfonyl)phenyl)-3-(thien-2-yl)-2,3-dihydro-4H-furo[3,2-c]chromen-4-one (2Ce). Pale yellow solid. M.p. 213.0–214.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.15 (dd, J = 8.0, 1.4 Hz, 1H), 7.74 (dd, J = 7.8, 1.6 Hz, 1H), 7.70 (dd, J = 7.6, 1.5 Hz, 1H), 7.67–7.57 (m, 3H), 7.44 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.27–7.23 (m, 1H), 7.05–7.00 (m, 2H), 6.96 (dd, J = 5.1, 3.5 Hz, 1H), 5.04 (d, J = 6.4 Hz, 1H), 2.87 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 166.16, 159.34, 155.62, 142.45, 138.74, 138.21, 134.85, 133.36, 130.28, 130.09, 128.48, 127.47, 126.31, 125.63, 124.37, 123.33, 117.33, 112.15, 105.00, 90.07, 50.58, 45.63. HRMS (ESI) m/z calculated [M + H]⁺ C₂₂H₁₇O₅S₂⁺ 425.0439, found 425.0442.

3.6. Extending the Coupling Methodology to Other Heterocyclic Phenols: 5-Hydroxyindole D and N,N′-Dimethylbarbituric Acid E

In a round-bottom flask, substrate 1 (0.157 mmol) was dissolved in CH₃CN/H₂O (97/3) (1.5 mL); then, 5-hydroxyindole D or N,N′-dimethylbarbituric acid E (0.157 mmol) and K₂CO₃ (0.157 mmol) were added. The reaction was stirred at 60 °C for the appropriate time. The crude was purified by column chromatography (petroleum ether/ethyl acetate 2:1, then 1:1 and 1:2). In the case of 5-hydroxyindole D, the expected dihydrofurans were always isolated in a mixture with minor quantities of the corresponding aromatized furan derivatives.

• 2-(2-(Methylsulfonyl)phenyl)-1-(p-tolyl)-1,6-dihydro-2H-furo[3,2-e]indole (2Da). ¹H NMR (CDCl₃, 400 MHz) δ 8.11 (s, 1H), 8.08 (dd, J = 8.0, 1.4 Hz, 1H), 7.79 (dd, J = 7.9, 1.3 Hz, 1H), 7.62 (td, J = 7.6, 1.4 Hz, 1H), 7.50 (ddd, J = 8.0, 7.4, 1.4 Hz, 1H), 7.28 (dt, J = 8.7, 0.9 Hz, 1H), 7.14 (d, J = 8.1 Hz, 2H), 7.10–7.06 (m, 3H), 6.87 (d, J = 8.6 Hz, 1H), 6.60 (d, J = 7.2 Hz, 1H,), 5.93 (ddd, J = 3.1, 2.0, 0.9 Hz, 1H), 4.94 (d, J = 7.2 Hz, 1H), 2.76 (s, 3H,), 2.29 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 153.51, 141.49, 138.62, 138.47, 136.94, 134.29, 132.61, 129.53, 129.44, 129.15, 128.92, 128.19, 125.78, 124.70, 118.42, 111.25, 105.42, 99.86, 87.23, 58.17, 45.37, 21.23. HRMS (ESI) m/z calculated [M + H]⁺ C₂₄H₂₂NO₃S⁺ 404.1242, found 404.1244.
• 8-(4-Methoxyphenyl)-7-(2-(methylsulfonyl)phenyl)-7,8-dihydro-1H-furo[2,3-g]indole (2Db). White solid. M.p. 119.0–120.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.14 (s, 1H), 8.08 (dd, J = 8.0, 1.4 Hz, 1H), 7.79 (dd, J = 7.9, 1.3 Hz, 1H), 7.62 (td, J = 7.6, 1.5 Hz, 1H), 7.55–7.45 (m, 1H), 7.28 (dt, J = 8.6, 0.9 Hz, 1H), 7.19–7.13 (m, 2H), 7.09 (t, J = 2.9 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 6.84–6.78 (m, 2H), 6.58 (d, J = 7.4 Hz, 1H), 5.92 (ddd, J = 3.1, 2.0, 0.9 Hz, 1H), 4.94 (d, J = 7.4 Hz, 1H), 3.75 (s, 3H), 2.78 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 158.86, 153.46, 141.45, 138.67, 134.28, 133.54, 132.62, 129.46, 129.39, 129.18, 128.92, 125.76, 124.67, 118.49, 114.18, 111.24, 105.44, 99.88, 87.28, 57.78, 55.27, 45.41. HRMS (ESI) m/z calculated [M + H]⁺ C₂₄H₂₂NO₄S⁺ 420.1191, found 420.1188.
• 8-(4-Chlorophenyl)-7-(2-(methylsulfonyl)phenyl)-7,8-dihydro-1H-furo[2,3-g]indole (2Dc). Always in mixture with 3Dc: ¹H-NMR peaks evaluated by subtraction. ¹H NMR (CDCl₃, 400 MHz) δ 8.23 (s, 1H), 8.08 (dd, J = 7.9, 1.5 Hz, 1H), 7.72 (dd, J = 7.9, 1.4 Hz, 1H), 7.64–7.56 (m, 1H), 7.56–7.45 (m, 1H), 7.29 (dt, J = 8.7, 1.0 Hz, 1H), 7.26–7.22 (m, 2H), 7.20–7.16 (m, 2H), 7.10 (t, J = 2.9 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 6.4 Hz, 1H), 5.92 (ddd, J = 3.1, 2.0, 1.0 Hz, 1H), 4.91 (d, J = 6.4 Hz, 1H), 2.93 (s, 3H).
• 7-(2-(Methylsulfonyl)phenyl)-8-(naphthalen-1-yl)-7,8-dihydro-1H-furo[2,3-g]indole (2Dd). White solid. M.p. 155.0–156.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.17 (s, 1H), 8.04 (dd, J = 8.0, 1.4 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.80–7.73 (m, 1H), 7.69 (td, J = 7.7, 1.4 Hz, 1H), 7.63–7.49 (m, 2H), 7.44–7.36 (m, 3H), 7.32 (d, J = 8.6 Hz, 1H), 7.29–7.21 (m, 1H), 7.07 (s, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.61 (d, J = 6.9 Hz, 1H), 5.96 (s, 1H), 5.79 (t, J = 2.6 Hz, 1H), 2.38 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 164.31, 153.88, 141.39, 139.00, 137.44, 134.47, 133.88, 133.83, 132.60, 131.91, 129.61, 129.18, 129.06, 127.80, 126.16, 125.76, 125.72, 124.68, 122.90, 117.88, 111.42, 105.79, 100.45, 87.52, 52.91, 44.94 (two isochronous carbons). HRMS (ESI) m/z calculated [M + H]⁺ C₂₇H₂₂NO₃S⁺ 440.1242, found 440.1235.
• 7-(2-(Methylsulfonyl)phenyl)-8-(thiophen-2-yl)-7,8-dihydro-1H-furo[2,3-g]indole (2De). White solid. M.p. 138.0–139.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.20 (s, 1H), 8.11 (dd, J = 7.9, 1.4 Hz, 1H), 7.74 (dd, J = 7.8, 1.4 Hz, 1H), 7.61 (td, J = 7.6, 1.5 Hz, 1H), 7.52 (td, J = 7.7, 1.4 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 7.19 (dd, J = 5.0, 1.4 Hz, 1H), 7.13 (t, J = 2.9 Hz, 1H), 6.97–6.90 (m, 2H), 6.85 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H), 6.11–6.03 (m, 1H), 5.32 (d, J = 7.4 Hz, 1H), 2.89 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 153.23, 144.70, 140.67, 138.91, 134.30, 132.71, 129.67, 129.16, 127.03, 126.00, 125.80, 124.91, 124.65, 117.70, 111.78, 105.46, 99.80, 87.49, 53.18, 45.42 (two isochronous carbons). HRMS (ESI) m/z calculated [M + H]⁺ C₂₁H₁₈NO₃S₂⁺ 396.0650, found 396.0659.
• 1,3-Dimethyl-6-(2-(methylsulfonyl)phenyl)-5-(p-tolyl)-5,6-dihydrofuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (2Ea). White solid. M.p. 284.0–285.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.03 (dd, J = 7.8, 1.2 Hz, 1H), 7.72–7.61 (m, 2H), 7.55 (ddd, J = 8.6, 6.4, 2.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 4.22–4.11 (m, 2H), 3.23 (s, 3H), 3.18 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 166.39, 165.69, 152.06, 139.56, 138.27, 133.97, 133.87, 132.12, 129.89, 129.59, 129.30, 129.11, 46.40, 43.78, 40.81, 28.93, 28.76, 21.37 (two isochronous carbons). HRMS (ESI) m/z calculated [M + H]⁺ C₂₂H₂₃N₂O₅S⁺ 427.1249, found 427.1238.
• 5-(4-Methoxyphenyl)-1,3-dimethyl-6-(2-(methylsulfonyl)phenyl)-5,6-dihydrofuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (2Eb). White solid. M.p. 108.0–109.0 °C. Mix stereoisomers. ¹H NMR (CDCl₃, 400 MHz) δ 8.08 (dd, J = 8.0, 1.4 Hz, 1H), 8.03 (dd, J = 8.1, 1.5 Hz, 1H), 7.70–7.61 (m, 3H), 7.58–7.51 (m, 1H), 7.51–7.43 (m, 2H), 7.33–7.26 (m, 4H), 6.95–6.85 (m, 4H), 5.74 (s, 2H), 4.19 (d, J = 9.4 Hz, 1H), 4.14 (d, J = 9.4 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.47 (s, 3H), 3.32 (s, 3H), 3.25 (s, 3H), 3.22 (s, 3H), 3.18 (s, 3H), 3.07 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 166.37, 165.65, 162.27, 160.53, 159.98, 159.62, 152.06, 151.74, 142.42, 139.54, 139.05, 134.68, 133.99, 133.86, 132.10, 130.62, 129.65, 129.58, 129.46, 129.37, 129.10, 128.27, 127.69, 124.69, 114.34, 113.93, 97.30, 91.56, 55.38, 55.36, 47.04, 46.49, 45.49, 43.78, 43.31, 40.77, 29.98, 28.92, 28.75, 28.10. HRMS (ESI) m/z calculated [M + H]⁺ C₂₂H₂₃N₂O₅S⁺ 443.1199, found 443.1190.
• 5-(4-Chlorophenyl)-1,3-dimethyl-6-(2-(methylsulfonyl)phenyl)-5,6-dihydrofuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (2Ec). White solid. M.p. 115.0–116.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.02 (d, J = 7.9 Hz, 1H), 7.68 (t, J = 7.5 Hz, 2H), 7.63 (d, J = 7.4 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 4.15 (s, 2H), 3.23 (s, 3H), 3.18 (s, 3H), 3.07 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 166.06, 165.65, 151.89, 139.59, 134.33, 133.88, 133.45, 132.06, 131.54, 130.77, 129.62, 129.30, 128.78, 45.20, 43.85, 41.09, 28.95, 28.81 (two isochronous carbons). HRMS (ESI) m/z calculated [M + H]⁺ C₂₁H₂₀ClN₂O₅S⁺ 447.0703, found 447.0709.
• 1,3-Dimethyl-6-(2-(methylsulfonyl)phenyl)-5-(naphthalen-1-yl)-5,6-dihydrofuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (2Ed). White solid. M.p. 245.0–246.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.08 (dd, J = 7.8, 1.3 Hz, 1H), 7.93–7.86 (m, 2H), 7.77–7.68 (m, 2H), 7.66–7.57 (m, 3H), 7.54–7.46 (m, 3H), 4.48 (d, J = 9.3 Hz, 1H), 4.34 (d, J = 9.3 Hz, 1H), 3.29 (s, 3H), 3.10 (s, 3H), 3.02 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 166.53, 165.38, 152.07, 139.71, 133.99, 133.92, 133.60, 132.37, 132.17, 129.69, 129.61, 129.35, 129.32, 129.29, 127.34, 127.11, 126.18, 125.29, 122.34, 44.16, 43.86, 41.14, 28.97, 28.80 (two isochronous carbons). HRMS (ESI) m/z calculated [M + H]⁺ C₂₅H₂₃N₂O₅S⁺ 463.1249, found 463.1240.
• 1,3-Dimethyl-6-(2-(methylsulfonyl)phenyl)-5-(thiophen-2-yl)-5,6-dihydrofuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (2Ee). Always in mixture with a minor unknown compound after chromatography. ¹H NMR (CDCl₃, 400 MHz) δ 8.02 (dd, J = 7.9, 1.3 Hz, 1H), 7.72–7.62 (m, 2H), 7.55 (ddd, J = 8.7, 6.8, 1.9 Hz, 1H), 7.29 (dd, J = 5.2, 1.2 Hz, 1H), 7.13 (d, J = 3.5 Hz, 1H), 7.01 (dd, J = 5.1, 3.6 Hz, 1H), 4.20 (s, 2H), 3.26 (s, 3H), 3.17 (s, 3H), 3.07 (s, 3H).

3.7. General Procedure for the Aromatization of 2Ba–e with DDQ

As already reported in [8], adequate conditions for N-heterocycles require only 2 mol equiv. of the oxidant DDQ, in CHCl₃ at room temperature; the desired furoquinoline was thus obtained within 24 h after chromatography in 91% yields. These successful conditions were then applied to all of the dihydrofuroquinolines prepared, furnishing generally good yields (73–99%) within 24–30 h. Only in the case of Ar = 1-Naphthyl, it was necessary to heat the reaction at reflux, employing 3 mol equiv. of DDQ.

• 3-(4-Methyphenyl)-2-(2-(methylsulfonyl)phenyl)furo[3,2-h]quinoline (3Ba). The compound was already characterized in [8].
• 3-(4-Methoxyphenyl)-2-(2-(methylsulfonyl)phenyl)furo[3,2-h]quinoline (3Bb). White solid. M.p. 146.5–147.7 °C (taken up with EP/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 8.92 (dd, J = 4.3, 1.7 Hz, 1H), 8.30–8.24 (m, 2H), 7.83 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.60 (td, J = 7.7, 1.5 Hz, 1H), 7.53 (td, J = 7.6, 1.5 Hz, 1H), 7.45 (dd, J = 8.3, 4.3 Hz, 1H), 7.43–7.37 (m, 3H), 6.96–6.88 (m, 2H), 3.81 (s, 3H), 3.62 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 159.23, 150.28, 149.35, 149.13, 141.19, 137.08, 136.42, 133.43, 133.34, 130.83, 130.66, 129.93, 128.04, 126.83, 123.66, 123.51, 120.75, 120.64, 120.03, 114.44, 55.35, 46.10 (two isochronous carbons). HRMS (ESI) m/z calculated [M + H]⁺ C₂₅H₂₀NO₄S⁺ 430.1235, found 430.1241.
• 3-(4-Chlorophenyl)-2-(2-(methylsulfonyl)phenyl)furo[3,2-h]quinoline (3Bc). The compound has been already characterized [8].
• 2-(2-(Methylsulfonyl)phenyl)-3-(naphth-1-yl)furo[3,2-h]quinoline (3Bd). White solid. M.p. 167.2–169.3 °C (taken up with EP/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 8.96 (dd, J = 4.4, 1.6 Hz, 1H), 8.27 (dd, J = 8.3, 1.7 Hz, 1H), 8.23 (dd, J = 8.0, 1.3 Hz, 1H), 7.97 (dd, J = 8.4, 1.1 Hz, 1H), 7.93–7.86 (m, 2H), 7.61 (d, J = 8.6 Hz, 1H), 7.57 (dd, J = 7.0, 1.3 Hz, 1H), 7.51–7.43 (m, 4H), 7.47–7.35 (m, 2H), 7.31 (td, J = 7.6, 1.3 Hz, 1H), 7.20 (dd, J = 7.7, 1.4 Hz, 1H), 3.77 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 151.00, 150.35, 149.27, 140.64, 137.16, 136.51, 133.89, 133.20, 132.62, 132.46, 130.72, 130.37, 129.82, 129.46, 129.37, 128.77, 128.72, 128.45, 126.99, 126.57, 126.19, 126.11, 125.82, 123.57, 120.83, 120.52, 119.69, 46.38. HRMS (ESI) m/z calculated [M + H]⁺ C₂₈H₂₀NO₃S⁺ 450.1086, found 450.1095.
• 2-(2-(Methylsulfonyl)phenyl)-3-(thien-2-yl)furo[3,2-h]quinoline (3Be). White solid. M.p. 146.5–147.7 °C (taken up with EP/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 8.93 (dd, J = 4.3, 1.7 Hz, 1H),8.32–8.26 (m, 2H), 8.02 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.71–7.63 (m, 2H), 7.62 (td, J = 7.3, 1.8 Hz, 1H), 7.47 (dd, J = 8.3, 4.3 Hz, 1H), 7.32 (dd, J = 5.1, 1.2 Hz, 1H), 7.15 (dd, J = 3.6, 1.2 Hz, 1H), 7.05 (dd, J = 5.1, 3.6 Hz, 1H), 3.44 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ150.44, 149.39, 149.32, 141.39, 136.91, 136.49, 133.72, 133.43, 132.47, 130.63, 130.56, 130.20, 127.65, 127.30, 127.08, 126.94, 125.91, 123.81, 120.99, 120.07, 115.16, 45.83. HRMS (ESI) m/z calculated [M + H]⁺ C₂₂H₁₆NO₃S₂⁺ 406.0493, found 406.0493.

3.8. General Procedure for Aromatization of 2Ca,b,c,e and 2Eb with DDQ

The relevant dihydrofuran (0.12 mmol) was dissolved in chloroform (3.0 mL) and DDQ (0.48 mmol) was added. The reaction was heated at 60 °C and maintained under magnetic stirring, until completion (monitored by TLC). Then, an aqueous saturated NaHCO₃ solution (8 mL) was added, and the resulting mixture was extracted with CHCl₃ (3 × 15 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The reaction mixture was purified by column chromatography (petroleum ether/ethyl acetate 1:1) to afford the desired aromatized products 3Ca,b,e, and 3Eb: as mentioned in footnote a of Table 6, 3Cc could be isolated only in admixture with 2Cc.

• 2-(2-(Methylsulfonyl)phenyl)-3-(p-tolyl)-4H-furo[3,2-c]chromen-4-one (3Ca). White solid. M.p. 135.0–136.0 °C (XX EtOH). ¹H NMR (CDCl₃, 400 MHz) δ 8.22 (dd, J = 7.9, 1.5 Hz, 1H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.65 (td, J = 7.7, 1.5 Hz, 1H), 7.61–7.50 (m, 2H), 7.47 (d, J = 8.3 Hz, 1H), 7.40–7.33 (m, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 3.16 (s, 3H), 2.31 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 157.58, 157.40, 152.92, 148.68, 140.83, 138.24, 134.20, 133.70, 131.13, 130.76, 130.68, 130.28, 129.14, 125.92, 124.61, 123.72, 120.61, 117.52, 112.73, 110.30, 45.24, 21.40 (two isochronous carbons). HRMS (ESI) m/z calculated [M + H]⁺ C₂₅H₁₉O₅S⁺ 431.0875, found 431.0868.
• 3-(4-Methoxyphenyl)-2-(2-(methylsulfonyl)phenyl)-4H-furo[3,2-c]chromen-4-one (3Cb). White solid. M.p. 113.0–114.0 °C (XX EtOH). ¹H NMR (CDCl₃, 400 MHz) δ 8.23 (dd, J = 7.9, 1.4 Hz, 1H), 7.78 (dd, J = 7.8, 1.5 Hz, 1H), 7.65 (td, J = 7.7, 1.5 Hz, 1H), 7.59 (td, J = 7.5, 1.5 Hz, 1H), 7.54 (ddd, J = 8.7, 7.2, 1.6 Hz, 1H), 7.48 (dd, J = 8.4, 1.2 Hz, 1H), 7.40–7.30 (m, 4H), 6.86–6.80 (m, 2H), 3.78 (s, 3H), 3.19 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 159.61, 157.70, 157.39, 152.90, 148.45, 140.81, 134.20, 133.75, 131.72, 131.14, 130.75, 130.72, 129.20, 124.63, 123.41, 121.10, 120.60, 117.54, 113.90, 112.74, 110.26, 55.31, 45.27. HRMS (ESI) m/z calculated [M + H]⁺ C₂₅H₁₉O₆S⁺ 447.0824, found 447.0818.
• 2-(2-(Methylsulfonyl)phenyl)-3-(thiophen-2-yl)-4H-furo[3,2-c]chromen-4-one (3Ce). White solid. M.p. 241.0–242.0 °C (XX EtOH). ¹H NMR (CDCl₃, 400 MHz) δ 8.29–8.23 (m, 1H), 7.83 (dd, J = 7.9, 1.6 Hz, 1H), 7.81–7.73 (m, 3H), 7.67–7.62 (m, 1H), 7.55 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.48 (dd, J = 8.5, 1.2 Hz, 1H), 7.34 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H), 7.20 (dd, J = 5.1, 1.2 Hz, 1H), 7.02 (dd, J = 5.1, 3.7 Hz, 1H), 2.91 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 157.87, 157.65, 152.94, 147.79, 141.33, 134.95, 133.88, 131.73, 131.44, 130.70, 130.64, 129.69, 128.80, 127.62, 126.68, 124.72, 121.08, 117.88, 117.34, 112.47, 109.29, 44.67. HRMS (ESI) m/z calculated [M + H]⁺ C₂₂H₁₅O₅S⁺ 423.0283, found 423.0290.
• 5-(4-Methoxyphenyl)-1,3-dimethyl-6-(2-(methylsulfonyl)phenyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (3Eb). White solid. M.p. 223.0–224.0 °C (XX EtOH). ¹H NMR (CDCl₃, 400 MHz) δ 8.25–8.19 (m, 1H), 7.71–7.63 (m, 2H), 7.43–7.37 (m, 1H), 7.21–7.14 (m, 2H), 6.78–6.72 (m, 2H), 3.75 (s, 3H), 3.67 (s, 3H), 3.32 (s, 3H), 2.96 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 159.64, 158.29, 154.20, 150.53, 146.24, 140.02, 134.17, 133.08, 131.34, 130.39, 129.82, 126.80, 121.37, 114.36, 99.71, 55.37, 44.42, 29.70, 28.33 (two isochronous carbons). HRMS (ESI) m/z calculated [M + H]⁺ C₂₂H₂₁N₂O₆S⁺ 441.1042, found 441.1038.

3.9. General Procedure for Aromatization of 2Da–e with DDQ

The relevant dihydrofuran 2D (0.12 mmol) was dissolved in toluene (3.0 mL) and DDQ (0.48 mmol) was added. The reaction was maintained under magnetic stirring, until completion (monitored by TLC). Then, an aqueous saturated NaHCO₃ solution (8 mL) was added, and the resulting mixture was extracted with CHCl₃ (3 × 15 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The reaction mixture was purified by column chromatography (petroleum ether/ethyl acetate 1:1) to afford the desired products 3Da–e.

• 7-(2-(Methylsulfonyl)phenyl)-8-(p-tolyl)-1H-furo[2,3-g]indole (3Da). White solid. M.p. 152.0–153.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.40 (s, 1H), 8.23 (dd, J = 7.9, 1.5 Hz, 1H), 7.54 (td, J = 7.7, 1.5 Hz, 1H), 7.47 (td, J = 7.5, 1.5 Hz, 1H), 7.44–7.40 (m, 2H), 7.35 (s, 2H), 7.32 (dd, J = 7.6, 1.5 Hz, 1H), 7.19–7.13 (m, 3H), 6.54 (dd, J = 3.2, 1.9 Hz, 1H), 3.37 (s, 3H), 2.37 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 150.05, 147.35, 140.64, 137.12, 133.95, 133.21, 132.66, 131.22, 130.30, 130.17, 129.73, 129.38, 129.20, 123.76, 121.23, 120.37, 120.33, 109.01, 105.96, 101.88, 45.15, 21.41. HRMS (ESI) m/z calculated [M + H]⁺ C₂₄H₂₀NO₃S⁺ 402.1086, found 402.1080.
• 8-(4-Methoxyphenyl)-7-(2-(methylsulfonyl)phenyl)-1H-furo[2,3-g]indole (3Db). White solid. M.p. 137.0–138.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.38 (s, 1H), 8.23 (dd, J = 7.9, 1.5 Hz, 1H), 7.54 (td, J = 7.7, 1.5 Hz, 1H), 7.51–7.43 (m, 3H), 7.34 (s, 2H), 7.32 (dd, J = 7.5, 1.5 Hz, 1H), 7.18–7.16 (m, 1H), 6.93–6.87 (m, 2H), 6.54 (dd, J = 3.2, 2.1 Hz, 1H), 3.82 (s, 3H), 3.38 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 159.04, 150.02, 147.25, 140.65, 133.94, 133.21, 132.65, 131.45, 131.24, 130.32, 129.36, 125.01, 123.81, 120.90, 120.41, 120.35, 113.96, 109.00, 105.98, 101.81, 55.31, 45.17. HRMS (ESI) m/z calculated [M + H]⁺ C₂₄H₂₀NO₄S⁺ 418.1035, found 418.11040.
• 8-(4-Chlorophenyl)-7-(2-(methylsulfonyl)phenyl)-1H-furo[2,3-g]indole (3Dc). White solid. M.p. 162.0–163.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.43 (s, 1H), 8.24 (dd, J = 7.9, 1.4 Hz, 1H), 7.57 (td, J = 7.7, 1.4 Hz, 1H), 7.54–7.45 (m, 3H), 7.37–7.30 (m, 4H), 7.27 (dd, J = 7.6, 1.4 Hz, 1H), 7.17 (d, J = 3.0 Hz, 1H), 6.49 (t, J = 2.5 Hz, 1H), 3.41 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 150.09, 147.80, 140.75, 133.85, 133.42, 133.39, 132.71, 131.61, 131.42, 130.78, 130.46, 129.72, 128.78, 124.03, 120.12, 119.89, 109.26, 105.94, 101.60, 45.30 (two isochronous carbons). HRMS (ESI) m/z calculated [M + H]⁺ C₂₃H₁₇ClNO₃S⁺ 422.0539, found 422.0537.
• 7-(2-(Methylsulfonyl)phenyl)-8-(naphthalen-1-yl)-1H-furo[2,3-g]indole (3Dd). White solid. M.p. 276.0–277.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.30 (s, 1H), 8.18 (dd, J = 8.0, 1.3 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.93–7.84 (m, 2H), 7.58 (dd, J = 7.0, 1.3 Hz, 1H), 7.51–7.29 (m, 6H), 7.30–7.21 (m, 1H), 7.17 (dd, J = 7.7, 1.4 Hz, 1H), 6.95 (t, J = 2.9 Hz, 1H), 5.59 (t, J = 2.5 Hz, 1H), 3.53 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 149.94, 148.94, 140.02, 133.74, 133.15, 133.00, 132.70, 132.55, 130.89, 130.51, 130.47, 129.30, 129.24, 128.31, 128.22, 126.70, 126.41, 126.05, 125.75, 123.85, 121.85, 120.50, 119.39, 109.16, 105.87, 101.73, 45.52. HRMS (ESI) m/z calculated [M + H]⁺ C₂₇H₂₀NO₃S⁺ 438.1086, found 438.1082.
• 7-(2-(Methylsulfonyl)phenyl)-8-(thiophen-2-yl)-1H-furo[2,3-g]indole (3De). White solid. M.p. 200.0–201.0 °C. ¹H NMR (CDCl₃, 400 MHz) δ 8.44 (1H, s), 8.25–8.20 (m, 1H), 7.64–7.54 (m, 2H), 7.52–7.47 (m, 1H), 7.37–7.33 (m, 2H), 7.30 (dd, J = 5.1, 1.2 Hz, 1H), 7.27–7.24 (m, 1H), 7.20 (t, J = 2.8 Hz, 1H), 7.06 (dd, J = 5.1, 3.5 Hz, 1H), 6.72 (dd, J = 3.2, 2.1 Hz, 1H), 3.24 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 150.00, 148.21, 140.87, 134.08, 133.41, 133.20, 132.79, 130.60, 130.16, 129.96, 128.31, 127.31, 126.04, 124.03, 120.09, 120.01, 114.81, 109.39, 106.02, 101.78, 44.91. HRMS (ESI) m/z calculated [M + H]⁺ C₂₁H₁₆NO₃S₂⁺ 394.0493, found 394.0497.

3.10. General Procedure for 6π-Electrocyclization of 3B and 3C

The relevant furan 3B or 3C (0.072 mmol) was dissolved in 3,5 mL of acetone (spectroscopic grade) and put in a 25 mL quartz tube; the tube was sealed, placed in a Rayonet photochemical reactor, and irradiated by UV light at 350 nm. The progress of the reaction was followed in TLC; after completion, the solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate) or crystallization. From the reactions, only the fully aromatized products 5B and 5C were isolated and characterized due to a fast methanesulfinic acid elimination (see Scheme 11).

• 9-Methylphenanthro[9′,10′:4,5]furo[3,2-h]quinoline (5Ba). White solid. M.p. 209.2–210.8 °C (taken up with EP/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 9.11 (d, J = 3.4 Hz, 1H), 8.82 (dd, J = 8.0, 1.6 Hz, 1H), 8.75 (d, J = 7.4 Hz, 1H), 8.61–8.54 (m, 2H), 8.51 (d, J = 8.6 Hz, 1H), 8.33 (dt, J = 8.2, 1.2 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.78–7.67 (m, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7.51 (dd, J = 8.4, 4.1 Hz, 1H), 2.67 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 151.50, 150.68, 150.42,137.06, 136.53, 135.11, 130.36, 130.28, 129.09, 128.99, 128.72, 127.25, 127.19, 126.84, 126.07, 124.98, 123.95, 123.89, 123.53, 123.41, 122.46, 122.27, 120.93, 22.16. HRMS (ESI) m/z calculated [M + H]⁺ C₂₄H₁₆NO⁺ 334.1154, found 334.1150.
• 9-Methoxyphenanthro[9′,10′:4,5]furo[3,2-h]quinoline (5Bb). White solid. M.p. 217.8–218.3 °C (taken up with EP/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 9.10 (dd, J = 4.3, 1.7 Hz, 1H), 8.80 (dd, J = 8.1, 1.5 Hz, 1H), 8.66 (dd, J = 8.1, 1.3 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.32 (dd, J = 8.3, 1.7 Hz, 1H), 8.17 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.75 (ddd, J = 7.9, 7.0, 1.4 Hz, 1H), 7.70 (ddd, J = 8.5, 7.0, 1.7 Hz, 1H) 7.50 (dd, J = 8.2, 4.2 Hz, 1H), 7.40 (dd, J = 8.8, 2.5 Hz, 1H), 4.05 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 157.53, 150.69, 150.65, 150.39, 137.04, 136.50, 130.10, 129.97, 127.46, 127.00, 126.84, 125.34, 124.80, 123.47, 123.44, 122.64, 122.53, 122.32, 120.91, 120.80, 116.83, 115.23, 106.19, 55.63. HRMS (ESI) m/z calculated [M + H]⁺ C₂₄H₁₆NO₂⁺ 350.1103, found 350.1110.
• 9-Chlorophenanthro[9′,10′:4,5]furo[3,2-h]quinoline (5Bc). White solid. M.p. 211.4–212.9 °C (taken up with EP/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 9.11 (d, J = 2.6 Hz, 1H), 8.81 (d, J = 7.8 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 8.1 Hz, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.44 (d, J = 8.6 Hz, 1H), 8.34 (dd, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.82–7.66 (m, 3H), 7.53 (dd, J = 8.3, 4.3 Hz, 1H). ¹³C NMR (CDCl₃, 101 MHz) δ 151.83, 150.84, 150.53, 137.00, 136.55, 131.51, 129.93, 129.53, 128.05, 127.84, 127.64, 126.99, 126.59, 125.38, 124.51, 123.86, 123.76, 123.49, 122.61, 122.36, 121.16, 120.56, 114.85. HRMS (ESI) m/z calculated [M + H]⁺ C₂₃H₁₃ClNO⁺ 354.0607, found 354.0601.
• Chryseno[5′,6′:4,5]furo[3,2-h]quinoline (5Bd). White solid. M.p. 261.1–262.9 °C (XX MeOH). ¹H NMR (CDCl₃, 400 MHz) δ 9.18–9.09 (m, 2H), 8.99–8.91 (m, 1H), 8.82–8.76 (m, 1H), 8.74 (d, J = 9.0 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.33 (dd, J = 8.2, 1.7 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.83–7.67 (m, 5H), 7.53 (dd, J = 8.2, 4.3 Hz, 1H). ¹³C NMR (CDCl₃, 101 MHz) δ 153.35, 150.96, 150.70, 137.22, 136.38, 132.94, 130.47, 129.84, 128.10, 127.66, 127.22, 127.08, 126.89, 126.83, 126.27, 125.94, 125.39, 125.16, 123.74, 122.88, 122.50, 122.17, 121.71, 121.21, 115.75 (two signals not visible because of isochrony). HRMS (ESI) m/z calculated [M + H]⁺ C₂₇H₁₆NO⁺ 370.1154, found 370.1158.
• Thieno[2″,3″:3′,4′]naphtho [2′,1′:4,5]furo[3,2-h]quinoline (5Be). White solid. M.p. 232.5–233.7 °C (taken up with EP/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 9.12 (dd, J = 4.3, 1.7 Hz, 1H), 8.90–8.81 (m, 1H), 8.50–8.41 (m, 1H), 8.35 (dd, J = 8.3, 1.7 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.76–7.67 (m, 2H), 7.66 (d, J = 5.3 Hz, 1H), 7.53 (dd, J = 8.2, 4.3 Hz, 1H). ¹³C NMR (CDCl₃, 101 MHz) δ 151.13, 150.76, 150.48, 136.96, 136.75, 133.58, 130.11, 128.79, 127.46, 127.04, 126.11, 124.44, 124.20, 123.79, 123.50, 122.50, 122.33, 121.08, 120.37, 120.01, 115.07. HRMS (ESI) m/z calculated [M + H]⁺ C₂₁H₁₂NOS⁺ 326.0561, found 326.0558.
• 9-Methyl-6H-phenanthro[9′,10′:4,5]furo[3,2-c]chromen-6-one (5Ca). White solid. M.p. 265.0–266.0 °C (taken up with EP/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 9.57 (d, J = 8.4 Hz, 1H), 8.64 (dd, J = 7.0, 2.3 Hz, 1H), 8.42 (s, 1H), 8.35 (dd, J = 7.5, 1.9 Hz, 1H), 8.09 (dd, J = 7.8, 1.6 Hz, 1H), 7.74–7.62 (m, 2H), 7.62–7.53 (m, 2H), 7.50 (dd, J = 8.5, 1.1 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 2.62 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 158.74, 158.61, 153.14, 150.02, 136.26, 131.34, 130.17, 129.38, 128.86, 128.07, 127.24, 124.67, 124.42, 123.51, 123.02, 121.57, 121.16, 120.83, 117.25, 117.19, 112.77, 108.51, 22.20 (two isochronous carbons). HRMS (ESI) m/z calculated [M + H]⁺ C₂₄H₁₅O₃⁺ 351.0943, found 351.0950.
• 9-Methoxy-6H-phenanthro[9′,10′:4,5]furo[3,2-c]chromen-6-one (5Cb). White solid. M.p. 250.0–251.0 °C (taken up with EP/DCM). ¹H NMR (CDCl₃, 400 MHz) δ 9.59 (d, J = 9.0 Hz, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.32 (dd, J = 7.5, 1.8 Hz, 1H), 8.07 (dd, J = 7.9, 1.6 Hz, 1H), 7.99 (d, J = 2.6 Hz, 1H), 7.69–7.60 (m, 2H), 7.58 (td, J = 7.9, 7.2, 1.6 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.34 (dd, J = 9.0, 2.6 Hz, 1H), 4.01 (s, 3H). ¹³C NMR (CDCl₃, 101 MHz) δ 158.70, 158.67, 158.21, 153.10, 149.24, 131.33, 130.39, 129.75, 127.46, 127.06, 124.68, 123.54, 121.55, 121.32, 120.86, 117.27, 117.18, 116.60, 112.77, 108.34, 105.55, 55.53 (two signals not visible because of isochrony). HRMS (ESI) m/z calculated [M + H]⁺ C₂₄H₁₅O₄⁺ 367.0892, found 367.0898.
• Crystal structure of 3Ca
• A single crystal of compound 3Ca was submitted to X-ray data collection on a Bruker APEX-II CCD diffractometer (Billerica, MA, USA) with a graphite monochromated Cu-Kα radiation (λ = 1.5418 Å) at 100 K. The structure was solved by direct methods implemented in the SHELXS-97 program [39]. The refinement was carried out by full-matrix anisotropic least squares on F 2 for all reflections for non-H atoms using the SHELXL-97 program (Version 2019/2) [40]. 3Ca crystallizes with a molecule of ethanol. Crystallographic data for this structure have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 2418973. Copies of the data can be obtained, free of charge, by application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; (fax: + 44-(0)-1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk).

4. Conclusions

By exploiting the double-coupling reaction between twofold (C/C) electrophilic molecules such as nitrostilbenes 1 and twofold (C/O) nucleophiles provided by an enol fragment within an aromatic phenolic ring such as B–E (Scheme 1 and Scheme 2 and Figure 2), a successful and quite robust synthesis of structurally different fused heteropolycycles, characterized by the presence of O or O and N heteroatoms, has been accomplished.

Following the initial double coupling to DHFs, further steps, namely, oxidative (DDQ) aromatization of the furan ring, 6π-electrocyclization, and full aromatization via methanesulfinic acid elimination, allow access to more complex, completely conjugated fused systems. For some of these systems, a significant fluorescence has been observed and measured and is applicable, e.g., in the field of optical devices.

Furthermore, on the grounds of both chemical diversity and/or spatial arrangement, biological/pharmacological activities are envisaged for at least some classes of molecules herein, which could also become leads for the design of new drugs. As a matter of fact, preliminary studies, in particular on furocoumarins, are quite promising, with results that still need completion and refinement and will be published in due time.

On the synthetic side, refined quantomechanical calculations fully rationalize on the grounds of both steric and electronic factors, in particular the complete failure of aromatization of 2Cd to 3Cd: a surely quite surprising result if compared, e.g., to the easy aromatization (in turn perfectly supported by quantomechanical calculations) of the 2Ad and 2Bd congeners.