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Article

A [3+3] Aldol-SNAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives

by
Kwabena Fobi
,
Ebenezer Ametsetor
and
Richard A. Bunce
*
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(14), 3406; https://doi.org/10.3390/molecules29143406
Submission received: 30 June 2024 / Revised: 16 July 2024 / Accepted: 18 July 2024 / Published: 20 July 2024
(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)
Browse Figures
Review Reports Versions Notes

Abstract

:
A one-pot [3+3] aldol-SNAr-dehydration annulation sequence was utilized to fuse hindered phenols onto aromatic substrates. The transformation joins doubly activated 1,3-disubstituted acetone derivatives (dinucleophiles) with C5-activated 2-fluorobenzaldehyde SNAr acceptors (dielectrophiles) in the presence of K2CO3 in DMF at 65–70 °C to form polysubstituted 2-naphthols and 7-hydroxyquinolines. The reaction is regioselective in adding the most stable anionic center to the aldehyde followed by SNAr closure of the less stabilized anion to the electron-deficient aromatic ring. Twenty-seven examples are reported, and a probable mechanism is presented. In two cases where SNAr activation on the acceptor ring was lower (a C5 trifluoromethyl group on the aromatic ring or a 2-fluoropyridine), diethyl 1,3-acetonedicarboxylate initiated an interesting Grob-type fragmentation to give cinnamate esters as the products.

Graphical Abstract

1. Introduction

An earlier report from the same laboratory used in this study outlined a [3+3] annulation to prepare 4H-1-benzopyrans [1]. Over the past decade, there have been many additional examples that utilized this strategy to generate a variety of complex molecules. We summarized a number of these reports in a recently published study that used a [3+3] approach to access quinolin-2(1H)-ones and 1,8-naphthyridine-2(1H)-ones [2]. The current work extends this method to the preparation of polysubstituted 2-naphthols and 7-hydroxyquinolines.
There are many commercially available 2-naphthol derivatives available at a relatively low cost, and synthetic transformations on the hydroxylated ring are quite facile. In addition to activating the OH-bearing ring through electron donation, the tautomeric nature of the OH group at C2 imparts significant nucleophilicity to C1. Thus, alkylations [3,4,5] and condensations [6,7,8,9,10] at C1 can be carried out under relatively mild conditions. Additionally, halogenation [11,12] and amination [13] procedures offer further strategies for functionalization at C1.
It is well established that 2-naphthol is an important scaffold in organic chemistry. It is a precursor to the BINOL system, which encompasses an important family of chiral ligands and catalysts [14] as well as some structures of biological importance [15,16]. Additionally, 2-naphthol is important in the synthesis of a wide variety of heterocyclic systems via multicomponent reactions [17,18].
Most modern syntheses of 2-naphthols involve the use of metal-promoted electrophilic [19,20,21], coupling [22], cycloaddition [23], or radical [24] approaches to effectively insert an ethene fragment between the terminus of a two-carbon side chain and the ortho carbon of an aryl ring. The current reaction permits the annulation of a substituted phenol to an appropriately substituted aromatic substrate. The process involves the stepwise addition of the two anions derived from a 1,3-disubstituted acetone (dinucleophile) to a C5-substituted 2-fluorobenzaldehyde derivative (dielectrophile) in a one-pot aldol-SNAr-dehydration sequence (see Scheme 1). This provides a straightforward synthesis of 2-naphthols without metal catalysts or other additives. This minimizes reaction optimization and problems associated with post-reaction metal contamination. One additional point of interest is the potential regioselectivity of the reaction when unsymmetrically substituted 1,3-disubstituted acetones are employed.
Recently, several 2-naphthol-based drug candidates have been reported in the literature. These derivatives expressed significant activity against cancer as well as Gram-positive and Gram-negative bacteria. While many active compounds have been disclosed, several of the most potent are depicted in Figure 1. Compound 1 demonstrated excellent activity (IC50 ≤ 1.2 μM) against Hep G2 (liver), A549 (lung), MDA-231 (breast), and HeLa (cervical) cancer cell lines [25]. Derivative 2 showed impressive GI50 values at concentrations of 1.46–2.90 μM against different strains of lung and breast cancers [26]. Compound 3 was found to inhibit 17β-hydroxysteroid dehydrogenases (17β-HSD1–89%) and 17β-HSD2 (61%) at a 1 μM concentration, which could favorably impact the treatment of estrogen-dependent diseases such as breast cancer and endometriosis [27]. Finally, structure 4 showed an IC50 value of 0.5 μg/mL in screens with S. aureus (Gram-positive) and a value of 2 μg/mL with E. coli (Gram-negative) bacteria [10].

2. Results and Discussion

The results of our study are summarized in Scheme 2 and Table 1, Table 2, Table 3 and Table 4. The Supplementary Materials give the 1H NMR and 13C NMR spectra for all new compounds. The reaction proceeded in the highest yield when 1 equiv. of the 2-fluorobenzaldehyde derivative (dielectrophile) was reacted with 2 equiv. of the 1,3-disubstituted acetone (dinucleophile) in the presence of 2 equiv. of anhydrous K2CO3 in dry DMF at 65–70 °C. Other combinations (1:1, 1.5:1, 2:1, and 1:1.5) of dielectrophile:dinucleophile gave lower yields. The reactants were mixed at room temperature (23 °C) and heated to 65–70 °C prior to the addition of the base. Further heating at this temperature for 6–12 h completed the reaction. Mild aqueous acid work-up and silica gel column chromatography (10–20% EtOAc in hexane) then delivered the purified products. C5 activation of the 2-fluorobenzaldehyde included resonance withdrawing (NO2, CN) and inductively withdrawing (CF3) groups; 2-fluoronicotinaldehyde was also explored as a dielectrophile. The 1,3-disubstituted acetones were substituted by ester, phenyl ketone, or phenylsulfonyl groups adjacent to the most acidic methylene with ester, phenyl ketone, or phenyl adjacent to the equivalent or less acidic site. Alkyl ketones failed in the reaction presumably due to their competitive enolization under the strong basic conditions. Successful examples proceeded in a high yield in a single laboratory operation. The reaction temperature and run time were based on our previous report [2]. The reactions were monitored by TLC and judged to be complete when all of the 2-fluorobenzaldehyde dielectrophile was consumed.
The 2-fluoroarylaldehyde derivatives 5a–d were commercially available, as were dimethyl and diethyl 1,3-acetonedicarboxylates 6 and 7, respectively. Other 1,3-disubstituted acetones were obtained by the use or adaptation of synthetic processes in the literature. The various methyl 4-aryl-3-oxobutanoates (8–14) were prepared by the general procedure reported for the synthesis of 4-phenyl-3-oxobutanoate by Yonemitsu and co-workers [28]. The method of Hauser et al. was used to access 1,3-dibenzoylacetone (15) [29]. The preparation of 1-phenyl-3-(phenylsulfonyl)propan-2-one (17) was accomplished by adapting the strategy developed by Nájera’s group for the synthesis of 1-phenyl-3-(p-tosyl)propan-2-one [30,31]. Finally, the synthesis of bis(benzenesulfonyl)propan-2-one (18) was accomplished using the procedure of Poli and co-workers [32].
An interesting feature of the reaction was the regioselectivity observed when unsymmetrical 1,3-disubstituted acetone derivatives were employed. For the substrates studied, the most acidic methylene was observed to attack the aldehyde, leaving the less acidic site to react with the aromatic ring in the final SNAr ring closure [33]. The process was promoted by K2CO3; no other catalysts or additives were required. Thus, the reactions predictably afforded a single product, making the yields higher and the final purifications less tedious.
A probable mechanism for the current reaction is given in Scheme 3 for the reaction of 2-fluoro-5-nitrobenzaldehyde (1a) with methyl 4-phenyl-3-oxobutanoate (8). The addition of the more stable β-ketoester anion to the aldehyde would give aldol product A. The subsequent deprotonation and reaction of the less acidic α-carbon at the fluorine-bearing site on the SNAr acceptor would close the ring to afford B. As previous work has demonstrated [2], this process requires a base to form the anion and an elevated temperature to promote the SNAr ring closure. The elimination of water from the initial ring-closed product B would then give enone C and tautomerization to the aromatic 2-naphthol 20. The late-stage loss of water would assure a favorable geometry for the ring closure of the anion derived from A.
In general, nitro-activated SNAr acceptor 5a gave the best results, followed by cyano-substituted substrate 5b. Dielectrophiles 5-trifluoromethyl-2-fluorobenzaldehyde (5c) and 2-fluoronicotinaldehyde (5d) were less reactive but also afforded annulation products with several of the dinucleophiles. Only one dinucleophile, 1,3-bis(phenylsulfonyl)propan-2-one (17), failed to give a [3+3] product in the nitro series (Table 1, entry 12). For this substrate, exposure to K2CO3 at 65–70 °C resulted in the decomposition of the bis(sulfone). Treatment with a milder tertiary amine base (Et3N) at the same temperature also resulted in the degradation of 17 but led to a respectable yield (82%) of 5-nitro-2-(phenylsulfonyl)benzaldehyde (29). The confirmation of the identity of 29 was accomplished by comparison with the same compound prepared from 2-fluoro-5-nitrobenzaldehyde and 2 equiv. of sodium benzenesulfinate in DMF containing 2 equiv. of Et3N at 65–70 °C for 30 min.
Finally, two examples involving reactions of the less-activated SNAr acceptors 5c and 5d with diethyl 1,3-acetonedicarboxylate (7) underwent elimination reactions to afford cinnamate ester products rather than the expected SNAr cyclization to produce 2-naphthol 37 and 7-hydroxyquinoline 40, respectively (entry 1 in Table 3 and Table 4). In these transformations, one can envision a base-initiated Grob-type fragmentation [34] (Scheme 4) with the loss of a malonate fragment in addition to hydroxide. The antiperiplanar alignment of these groups should facilitate this elimination to the stable conjugated ester product.

3. Materials and Methods

3.1. General Methods

Unless otherwise indicated, all reactions were performed under dry N2 in dry glassware. All commercial reagents and solvents were used as received (Combi Blocks, San Diego, CA, USA and Fisher Scientific, Pittsburgh, PA, USA). All wash solutions employed in work-up procedures were aqueous. Reactions were followed by thin layer chromatography on Analtech No 21521 silica gel GF plates (Newark, DE, USA). Preparative separations were accomplished by column chromatography on Davisil®, grade 62, 60–200-mesh silica gel containing 0.5% of UV-05 phosphor (both from Sorbent Technologies, Norcross, GA, USA) slurry packed into quartz columns. Band elution for all chromatographic separations was monitored using a hand-held ultraviolet lamp (Fisher Scientific, Pittsburgh, PA, USA). Melting points (uncorrected) were obtained using a MEL-TEMP apparatus (Cambridge, MA, USA). FT-IR spectra were run as thin films on sodium chloride disks or in ATR mode using a Nicolet iS50 spectrophotometer (Madison WI, USA). 1H- and 13C-NMR spectra were obtained using a Bruker Avance 400 system (Billerica, MA, USA) at 400 MHz and 101 MHz, respectively, in CDCl3 or DMSO-d6 containing 0.05% tetramethylsilane as the internal standard (Cambridge Isotope Laboratories, Andover, MA, USA). Chemical shifts are given in ppm downfield from the internal standard, and coupling constants (J) are reported in Hz. Low-resolution mass spectra were obtained using a Hewlett-Packard Model 1800A GCD GC-MS system (Palo Alto, CA, USA). Elemental analyses (±0.4%) on all new compounds were carried out by Atlantic Microlabs (Norcross, GA, USA).
β-Ketoesters 8–14 were prepared from 5 g each of the substituted phenylacetyl chloride derivatives according to the procedure used by Yonemitsu and co-workers [29]. 1,3-Dibenzoylacetone (15) was prepared on a 25 mmol scale using the method by Hauser et al. [30]. The remaining 1,3-disubstituted acetones required multistep procedures. Several of these dinucleophiles are known, but the spectra were not always provided in the past. Some contain varying amounts of the corresponding enols.

3.2. Methyl 3-Oxo-4-phenylbutanoate (8)

Yield: 5.09 g (82%) as a colorless oil, b.p. 92–96 °C at 0.05 mm Hg (reference [28], b.p. 126–128 °C at 0.6 mm Hg); IR: 1745, 1721 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.37–7.25 (complex, 3H), 7.21 (dm, J = 7.4 Hz, 2H), 3.82 (s, 2H), 3.71 (s, 3H), 3.47 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 200.4, 167.6, 133.2, 129.6, 128.9, 127.4, 52.4, 50.1, 48.0; MS (m/z): 192 (C11H12O3, M+).

3.3. Methyl 4-(2-Fluorophenyl)-3-oxobutanoate (9)

Yield: 4.14 g (68%) as a colorless oil, b.p. 95–98 °C (0.08 mm Hg); IR: 1746, 1722, 1235 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.27 (m, 1H), 7.19 (td, J = 7.6, 1.9 Hz, 1H), 7.13–7.03 (complex, 2H), 3.87 (s, 2H), 3.72 (s, 3H), 3.53 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 199.2 167.5, 161.0 (d, J = 246.1 Hz), 131.8 (d, J = 4.1 Hz), 129.4 (d, J = 6.5 Hz), 124.4 (d, J = 3.6 Hz), 120.7 (d, J = 16.1 Hz), 115.5 (d, J = 21.7 Hz), 52.4, 48.2, 43.1 (d, J = 2.5 Hz); MS (m/z): 210 (C11H11FO3, M+).

3.4. Methyl 4-(4-Chlorophenyl)-3-oxobutanoate (10)

Yield: 4.19 g (70%) as a colorless oil, b.p. 117–121 °C (0.01 mm Hg); IR: 1748, 1725 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 3.81 (s, 2H), 3.73 (s, 3H), 3.47 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 199.7, 167.4, 133.4, 131.5, 130.9, 129.0, 52.4, 49.1, 48.2; MS (m/z): 226, 228 (C11H11ClO3, ca. 3:1 M+).

3.5. Methyl 4-(4-Methylphenyl)-3-oxobutanoate (11)

Yield: 4.52 (74%) as a colorless oil, b.p. 104–107 °C (0.01 mm Hg); IR: 1745, 1719 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.15 (d, J = 8.1 Hz, 2H), 7.09 (s, J = 8.1 Hz, 2H), 3.77 (s, 2H), 3.71 (s, 3H), 3.44 (s, 2H), 2.33 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 200.7, 167.6, 137.1, 130.1, 129.6, 129.4, 52.4, 49.7, 47.9, 21.1; MS (m/z): 206 (C12H14O3, M+).

3.6. Methyl 4-(4-Methoxyphenyl)-3-oxobutanoate (12)

Yield: 4.81 g (80%) as a colorless oil, b.p. 121–25 °C (0.01 mm Hg); IR: 2839, 1747, 1724 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.12 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 2H), 3.71 (s, 3H), 3.45 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 200.8, 167.3, 158.9, 130.6, 125.1, 114.3, 55.3, 52.4, 49.2, 47.8; MS (m/z): 222 (C12H14O4, M+).

3.7. Methyl 3-Oxo-4-(3-(trifluoromethyl)phenyl)butanoate (13)

Yield: 3.62 g (62%) as a colorless oil, b.p. 121–125 °C (0.01 mm Hg); IR: 1749, 1725 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.55 (m, 1H), 7.44 (m, 2H), 7.40 (m, 1H), 3.92 (s, 2H), 3.71 (s, 3H), 3.52 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 199.6, 167.5, 134.1, 133.2, 129.2, 126.4 (q, J = 3.9 Hz), 124.1 (q, J = 4.0 Hz), 124.0 (q, J = 272.3 Hz), 52.4, 49.1, 48.3; MS (m/z): 260 (C12H11F3O3, M+).

3.8. Methyl 4-(2,5-Dimethylphenyl)-3-oxobutanoate (14)

Yield: 5.12 g (85%) as a colorless oil that solidified to a waxy solid, b.p. 108–112 °C (0.001 mm Hg); IR: 1747, 1720 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.07 (d, J = 7.7 Hz, 1H), 7.01 (dd, J = 7.7, 1.9 Hz, 1H), 6.94 (d, J = 1.9 Hz, 1H), 3.79 (s, 2H), 3.71 (s, 3H), 3.44 (s, 2H), 2.30 (s, 3H), 2.19 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 200.5, 167.6, 135.9, 133.9, 131.8, 131.2, 130.5, 128.4, 52.3, 48.4, 47.9, 20.9, 19.1; MS (m/z): 220 (C13H16O3, M+).

3.9. 1,3 Dibenzoylpropan-2-One (15)

Yield: 5.32 g (80%) as a yellow solid, m.p. 105–108 °C (lit [29] m.p. 105–109 °C); IR: 3194–2990, 1682, 1600, 1552, 1496 cm−1; 1H NMR (400 MHz, CDCl3): δ 14.76 (s, 2H), 7.86 (dm, J = 6.9 Hz, 4H), 7.53–7.42 (complex, 6H), 6.02 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 194.1, 173.7, 133.7, 131.7, 128.6, 126.4, 96.8; MS (m/z): 266 (C17H14O3, M+).

3.10. 1-Phenyl-3-(Phenylsulfonyl)propan-2-one (16)

Yield: 0.88 g (32%, 3 steps) as a white solid, m.p. 82–83 °C; IR: 1716, 1314, 1136 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 7.9 Hz, 2H), 7.67 (m, 1H), 7.57 (t, J = 7.9 Hz, 2H), 7.36–7.26 (complex, 3H), 7.19 (d, J = 7.9 Hz, 2H), 4.16 (s, 2H), 3.98 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 195.7, 134.4, 129.7, 129.4, 129.1, 128.7, 128.3, 127.9, 127.7, 65.6, 50.9; MS (m/z): 274 (C15H14O3S, M+).

3.11. 1,3 Bis(Phenylsulfonyl)propan-2-one (17)

Yield: 0.56 g (10%) as an off-white solid, m.p. 156–158 °C (lit [32] m.p. 157–159 °C); IR: 1732, 1341, 1150 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.85 (dm, J = 7.5 Hz, 4H), 7.71 (tt, J = 7.5, 1.8 Hz, 2H), 7.58 (tt, J = 7.5, 1.8 Hz, 4H), 4.51 (s, 4H); 13C NMR (101 MHz, CDCl3): δ 186.4, 138.2, 134.7, 129.6, 128.3, 67.6; MS (m/z): 338 (C15H14O5S2, M+).

3.12. Representative Procedure for the [3+3] Preparation of Hindered 2-Naphthols

The 1,3-disubstituted acetone (2 equiv.) was added to a solution of the C5-substituted 2-fluorobenzaldehyde derivative (1.0–1.2 mmol, 1 equiv.) in DMF (10 mL) under N2. The mixture was stirred for 5 min at 23 °C and then for 15 min at 65–70 °C prior to the addition of anhydrous K2CO3 (2 equiv.). Heating was continued until TLC (20% EtOAc in hexane) indicated complete consumption of the starting materials (6–12 h). The mixture was poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with 1 M HCl (2 × 30 mL), saturated NaHCO3 (1 × 30 mL), and saturated NaCl (1 × 30 mL), and then dried (Na2SO4) and filtered. The crude product was concentrated under a vacuum, and the resulting oil/solid was purified by column chromatography eluted with 10–20% EtOAc in hexane to give the pure products. The following compounds were prepared:

3.12.1. Dimethyl 2-Hydroxy-6-nitronaphthalene-1,3-dicarboxylate (18)

Yield: 0.32 g (89%) as a white solid, m.p. 187–189 °C; IR: 3240–2980, 1726, 1683, 1533, 1342 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.59 (s, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.74 (s, 1H), 8.33 (dd, J = 9.4, 2.4 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 4.10 (s, 3H), 4.09 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 168.8, 167.1, 158.1, 144.2, 137.0, 136.9, 126.4, 125.7, 124.9, 123.5, 116.7, 115.8, 53.4, 53.0; MS m/z: 305 (M+); Anal. Calcd for C14H11NO7: C, 55.09; H, 3.63; N, 4.59; found: C, 55.12; H, 3.64; N 4.51.

3.12.2. Diethyl 2-Hydroxy-6-nitronaphthalene-1,3-dicarboxylate (19)

Yield: 0.35 g (88%) as a white solid, m.p. 130–131 °C; IR: 3435, 1722, 1504, 1334 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.62 (s, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.74 (s, 1H), 8.33 (dd, J = 9.4, 2.4 Hz, 1H), 8.02 (d, J = 9.4 Hz, 1H), 4.55 (overlapping q, J = 7.1 Hz, 4H), 1.51 (overlapping t, J = 7.1 Hz, 6H); 13C NMR (101 MHz, CDCl3): δ 168.5, 166.6, 158.0, 144.1, 136.8, 136.6, 126.4, 125.6, 124.9, 123.3, 116.9, 116.3, 62.8, 62.2, 14.3, 14.2; MS: (m/z): 333 (M+); Anal. Calcd for C16H15NO7: C, 57.66; H, 4.54; N, 4.20; found: C, 57.64; H, 4.52; N, 4.13.

3.12.3. Methyl 3-Hydroxy-7-nitro-4-phenyl-2-naphthoate (20)

Yield: 0.32 g (89%) as a yellow solid, m.p. 201–203 °C; IR: 3300–2960, 1683, 1621, 1530, 1333 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.10 (s, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.75 (s, 1H), 8.13 (dd, J = 9.4, 2.4 Hz, 1H), 7.60 (d, J = 9.4 Hz, 1H), 7.56 (t, J = 7.3 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H), 7.38 (d, J = 7.2 Hz, 2H), 4.09 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 169.9, 156.4, 143.9, 139.1, 134.18, 134.16, 130.7, 128.7, 128.1, 126.7, 126.5, 125.1, 125.0, 122.0, 115.8, 53.2; MS (m/z): 323 (M+); Anal. Calcd for C18H13NO5: C, 66.87; H, 4.05; N, 4.33; found: C, 66.79; H, 4.01; N, 4.26.

3.12.4. Methyl 4-(2-Fluorophenyl)-3-hydroxy-7-nitro-2-naphthoate (21)

Yield: 0.37 g (93%) as a light pink solid, m.p. 180–181 °C; IR: 3433, 1730, 1520, 1344, 1219 cm−1; 1H NMR (400 MHz, CDCl3): δ 13.09 (s, 1H), 8.90 (d, J = 9.6 Hz, 1H), 8.70 (d, J = 2.5 Hz, 1H), 8.33 (dd, J = 9.6, 2.5 Hz, 1H), 8.08 (s, 1H), 7.48–7.42 (complex, 2H), 7.30–7.20 (complex, 2H), 4.18 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 172.4, 165.1, 160.1 (d, J = 248.5 Hz), 143.6, 138.8 (d, J = 1.5 Hz), 135.1, 131.6 (d, J = 3.1 Hz), 130.5 (d, J = 8.3 Hz), 129.1, 126.9, 126.7, 125.3, 124.1 (d, J = 3.7 Hz), 123.7 (d, J = 15.6 Hz), 121.8, 115.8 (d, J = 22.1 Hz), 105.4, 53.2; MS (m/z): 341 (M+); Anal. Calcd for C18H12FNO5: C, 63.35; H, 3.54; N, 4.10; found: C, 63.41; H, 3.55; N, 4.04.

3.12.5. Methyl 4-(4-Chlorophenyl)-3-hydroxy-7-nitro-3-naphthoate (22)

Yield: 0.40 g (94%) as a yellow solid, m.p. 166–167 °C; IR: 3198–2735, 1691, 1504, 1336 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 9.21 (d, J = 2.5 Hz, 1H), 9.05 (s, 1H), 8.21 (dd, J = 9.5, 2.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 9.5 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 4.04 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 169.8, 156.4 144.0, 138.9, 134.5, 132.6, 132.1, 130.9, 129.0, 128.6, 126.6, 126.3, 125.0, 122.3, 115.9, 53.3; MS (m/z): 357, 359 (ca. 3:1, M+); Anal. Calcd for C18H12ClNO5: C, 60.43; H, 3.38; N, 3.92; found: C, 60.35; H, 3.36; N, 3.89.

3.12.6. Methyl 3-Hydroxy-4-(4-methylphenyl)-7-nitro-3-naphthoate (23)

Yield: 0.36 g (91%) as an orange solid, m.p. 170–171 °C; IR: 3485, 1728, 1529, 1344 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.16 (dd, J = 8.9 Hz, 1H), 8.00 (d, J = 2.7 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.21 (s, 1H), 7.18 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.9 Hz, 1H), 6.66 (s, 1H), 3.91 (s, 3H), 2.37 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 164.0, 158.4, 143.3, 143.1, 137.3, 131.6, 129.5, 129.3, 129.2, 127.6, 126.1, 123.4, 120.4, 115.6, 110.0, 52.7, 21.4; MS (m/z): 337 (M+); Anal. Calcd for C19H15NO5: C, 67.65; H, 4.48; N, 4.15; found: C, 67.57; H, 4.47; N, 4.11.

3.12.7. Methyl 3-Hydroxy-4-(4-methoxyphenyl)-7-nitro-3-naphthoate (24)

Yield: 0.40 g (96%) as a light yellow solid, m.p. 198–199 °C; IR: 3404, 2844, 1729, 1518, 1337 cm−1; 1H NMR (400 MHz, CDCl3): δ 13.2 (s, 1H), 8.86 (d, J = 9.6 Hz, 1H), 8.70 (d, J = 2.5 Hz, 1H), 8.29 (dd, J = 9.6, 2.5 Hz, 1H), 8.05 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 4.18 (s, 3H), 3.89 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 172.7, 165.3, 159.8, 143.6, 137.3, 134.5, 134.0, 130.7, 128.2, 127.2, 126.6, 125.1, 121.3, 113.9, 105.4, 55.4, 53.1; MS (m/z): 353 (M+); Anal. Calcd for C19H15NO6: C, 64.59; H, 4.28; N, 3.96; found: C, 64.52; H, 4.29; N, 3.93.

3.12.8. Methyl 3-Hydroxy-7-nitro-4-(3-(trifluoromethyl)phenyl)-2-naphthoate (25)

Yield: 0.35 g (85%) as a white solid, m.p. 182–183 °C; IR: 3423, 1728, 1534, 1339 cm−1; 1H NMR (400 MHz, CDCl3): δ 13.23 (s, 1H), 8.90 (d, J = 9.6 Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.34 (dd, J = 9.6, 2.5 Hz, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 4.20 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 172.5, 164.7, 143.8, 137.9, 136.7, 134.9, 132.9, 132.8, 131.9 (q, J = 32.5 Hz), 128.9, 127.1, 126.8, 126.4 (q, J = 4.0 Hz), 125.3, 125.1 (q, J = 3.8 Hz), 124.1 (q, J = 272.5 Hz), 122.0, 105.7, 53.3; MS (m/z): 391 (M+); Anal. Calcd for C19H12F3NO5: C, 58.32; H, 3.09; N, 3.58; found: C, 58.26; H, 3.05; N, 3.61.

3.12.9. Methyl 4-(2,5-Dimethylphenyl)-3-hydroxy-7-nitro-2-naphthoate (26)

Yield: 0.40 g (96%) as an orange solid, m.p. 180–181 °C; IR: 3439, 1726, 1528, 1345 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.15 (dd, J = 9.0, 2.6 Hz, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.68 (s, 1H), 7.35 (s, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.00 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.85 (s, 1H), 3.92 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 164.0, 158.4, 143.3, 143.0, 134.9, 133.8, 132.8, 130.2, 130.1, 129.3, 128.1, 127.7, 125.8, 123.4, 120.4, 115.6, 108.0, 52.7, 21.3, 20.0; MS (m/z): 351 (M+); Anal. Calcd for C20H17NO5: C, 68.37; H, 4.88; N, 3.99; found: C, 68.39; H, 4.88; N, 3.91.

3.12.10. 1,3 Dibenzoyl-2-Hydroxy-6-nitronaphthalene (27)

Yield: 0.41 g (87%) as a light yellow solid, m.p. 140–141 °C; IR: 3280–2920, 1667, 1633, 1526, 1339 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.71 (s, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.52 (s, 1H), 8.25 (dt, J = 9.4, 2.3 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 8.5 Hz, 2H), 7.74 (t, J = 7.4 Hz, 1H), 7.71–7.59 (complex, 4H), 7.50 (t, J = 7.6 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 200.9, 195.5, 157.6, 144.3, 139.6, 137.4, 137.1, 136.8, 134.3, 133.4, 129.7, 129.0, 128.9, 126.8, 125.5, 124.9, 123.7, 123.2, 122.1 (one carbon unresolved); MS (m/z): 397 (M+); Anal. Calcd for C24H15NO5: C, 72.54; H, 3.80; N, 3.52; found: C, 72.47; H, 3.79; N, 3.45.

3.12.11. 6-Nitro-1-Phenyl-3-(phenylsulfonyl)-2-naphthol (28)

Yield: 0.43 g (89%) as a yellow solid, m.p. 155–156 °C; IR: 3498, 1344, 1150 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.85 (d, J = 2.4 Hz, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.16 (dd, J = 9.4, 2.3 Hz, 1H), 8.07–8.04 (complex, 2H), 7.65 (m, 1H), 7.59–7.53 (complex, 6H), 7.35–7.32 (complex, 2H); 13C NMR (101 MHz, CDCl3): δ 150.3, 144.5, 140.5, 139.0, 134.3, 133.1, 132.8, 130.6, 129.6, 129.12, 129.06, 128.8, 127.6, 127.1, 126.5, 126.2, 125.8, 122.5; MS (m/z): 405 (M+); Anal. Calcd for C22H15NO5S: C, 65.18; H, 3.73; N, 3.45; found: C, 65.09; H, 3.72; N, 3.39.

3.12.12. 5-Nitro-2-(Phenylsulfonyl)benzaldehyde (29)

The dinucleophile 1,3-bis(phenylsulfonyl)propan-2-one (17) decomposed under the standard conditions (2 equiv. of K2CO3 in DMF at 65–70 °C). When Et3N (2 equiv.) was employed as the base in DMF at the same temperature, 29 was produced in a good yield after 30 min. Yield: 0.38 g (82%) as a white solid, m.p. 94–95 °C; IR: 1698, 1531, 1344, 1324, 1153 cm−1; 1H NMR (400 MHz, CDCl3): δ 10.90 (s, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.55 (dd, J = 8.6, 2.4 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.70 (tt, J = 7.7, 1.3 Hz, 1H), 7.61 (t, J = 7.7 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 187.0, 150.8, 147.4, 140.0, 135.5, 134.7, 131.2, 130.1, 127.9, 127.7, 124.6; MS (m/z): 291 (M+); Anal. Calcd for C13H9NO5S: C, 53.61; H, 3.11; N, 4.81; found: C, 53.65; H, 3.13; N, 4.77. The product was independently prepared by treating 5a with 2 equiv. of 17 in DMF using 2 equiv. of Et3N at 65–70 °C for 30 min. The spectral data were identical.

3.12.13. Dimethyl 6-Cyano-2-hydroxynaphthalene-1,3-dicarboxylate (30)

Yield: 0.32 g (84%) as a white solid, m.p. 183–184 °C; IR: 3220–2975, 2228, 1732, 1671 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.50 (s, 1H), 8.60 (s, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.69 (dd, J = 8.9, 1.7 Hz, 1H), 4.08 (s, 3H), 4.07 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 168.9, 167.1, 157.6, 135.72, 135.65, 135.6, 130.4, 125.42, 125.38, 118.5, 116.3, 115.6, 108.2, 53.3, 52.9; MS (m/z): 285 (M+); Anal. Calcd for C15H11NO5: C, 63.16; H, 3.89; N, 4.91; found: C, 63.13; H, 3.87; N, 4.85.

3.12.14. Methyl 7-Cyano-3-hydroxy-4-phenyl-2-naphthoate (31)

Yield: 0.34 g (83%) as a white solid, m.p. 190–191 °C; IR: 3240–2900, 2227, 1653 cm−1; 1H NMR (400 MHz, CDCl3): δ 13.10 (s, 1H), 8.84 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.96 (s, 1H), 7.71 (dd, J = 9.1, 1.9 Hz, 1H), 7.62 (d, J = 7.4 Hz, 2H), 7.53–7.42 (complex, 3H), 4.17 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 172.7, 164.6, 136.6, 136.1, 134.5, 134.0, 133.3, 129.5, 129.0, 128.4, 128.3, 127.4, 126.4, 119.0, 107.5, 105.2, 53.0; MS (m/z): 303 (M+); Anal. Calcd for C19H13NO3: C, 75.24; H, 4.32; N, 4.62; found: C, 75.23; H, 4.29; N, 4.57.

3.12.15. Methyl 7-Cyano-4-(2-fluorophenyl)-3-hydroxy-2-naphthoate (32)

Yield: 0.40 g (92%) as an orange solid, m.p. 179–180 °C; IR: 3205–2895, 2234, 1724 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.05 (td, J = 7.7, 1.8 Hz, 1H), 7.56 (dd, J = 8.5, 2.0 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.32 (s, 1H), 7.25–7.19 (complex, 1H), 7.15 (td, J = 7.6, 1.5 Hz, 1H), 7.10–7.04 (complex, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.88 (s, 1H), 3.92 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 163.9, 160.1 (d, J = 250.1 Hz), 156.5, 144.8 (d, J = 2.5 Hz), 135.8, 131.9, 130.4, 129.6 (d, J = 2.5 Hz), 128.5 (d, J = 8.5 Hz), 125.6, 123.8 (d, J = 3.6 Hz), 122.6 (d, J = 11.7 Hz), 120.8, 118.0, 116.3, 115.2 (d, J = 22.5 Hz), 106.9, 100.7 (d, J = 7.8 Hz), 52.8; MS (m/z): 321 (M+); Anal. Calcd for C19H12FNO3: C, 71.03; H, 3.76; N, 4.36; found: C, 70.97; H, 3.78; N, 4.33.

3.12.16. Methyl 4-(4-Chlorophenyl)-7-cyano-3-hydroxy-2-naphthoate (33)

Yield: 0.42 g (92%) as a white solid, m.p. 240–241 °C; IR: 3230–2875, 2227, 1718 cm−1; 1H NMR (400 MHz, CDCl3): δ 13.12 (s, 1H), 8.84 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.94 (s, 1H), 7.71 (dd, J = 9.1, 1.9 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 4.17 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 172.6, 164.3, 136.5, 134.52, 134.49, 134.45, 133.4, 132.8, 130.9, 129.2, 128.6, 127.4, 126.5, 118.9, 107.5, 105.4, 53.1; MS (m/z): 337, 339 (ca. 3:1, M+); Anal. Calcd for C19H12ClNO3: C, 67.57; H, 3.58; N, 4.15; found: C, 67.54; H, 3.56; N, 4.08.

3.12.17. Methyl 7-Cyano-3-hydroxy-4-(4-methoxyphenyl)-2-naphthoate (34)

Yield: 0.42 g (94%) as a white solid, m.p. 198–199 °C; IR: 3184–2895, 2838, 1719 cm−1; 1H NMR (400 MHz, CDCl3): δ 13.12 (s, 1H), 8.82 (d, J = 9.1 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.93 (s, 1H), 7.68 (dd, J = 9.1, 1.9 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 8.2 Hz, 2H), 4.16 (s, 3H), 3.88 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 172.8, 164.7, 159.7, 136.6, 134.4, 133.6, 133.1, 130.7, 128.8, 128.4, 127.5, 126.4, 119.1, 113.9, 107.3, 105.2, 55.4, 53.0; MS (m/z): 333 (M+); Anal. Calcd for C20H15NO4: C, 72.06; H, 4.54; N, 4.20; found: C, 72.02; H, 4.54; N, 4.14.

3.12.18. Methyl 7-Cyano-3-hydroxy-4-(2,5-dimethylphenyl)-2-naphthoate (35)

Yield: 0.42 g (95%) as an orange solid, m.p. 164–165 °C; IR: 3210–2900, 2225, 1717 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.52 (dd, J = 8.4, 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.27 (s, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 3.91 s, 3H), 2.36 (s, 3H), 2.32 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 164.1, 156.9, 143.3, 135.8, 134.8, 133.7, 132.9, 131.7, 130.01, 129.99, 129.3, 128.0, 125. 7, 121.0, 118.2, 116.2, 107.4, 106.5, 52.6, 21.3, 20.0; MS (m/z): 331 (M+); Anal. Calcd for C21H17NO3: C, 71.99; H, 4.89; N, 4.00; found: C, 72.00; H, 4.88; N, 3.94.

3.12.19. 5,7 Dibenzoyl-6-hydroxy-2-naphthonitrile (36)

Yield: 0.40 g (80%) as a yellow solid, m.p. 135–136 °C; IR: 3250–2940, 2226, 1662, 1631 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.61 (s, 1H), 8.37 (s, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.92 (m, 2H), 7.80 (m, 2H), 7.73 (tt, J = 7.5, 1.3 Hz, 1H), 7.68–7.58 (complex, 5H), 7.49 (t, J = 7.3 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 201.0, 195.6, 156.9, 138.1, 137.2, 136.9, 136.2, 136.1, 134.2, 133.3, 130.6, 129.68, 129.65, 128.94, 128.88, 125.4, 125.3, 123.0, 121.8, 118.4, 108.2; MS (m/z): 377 (M+); Anal. Calcd for C25H15NO3: C, 79.56; H, 4.01; N, 3.71; found: C, 79.49; H, 4.00; N, 3.69.

3.12.20. Ethyl (E)-3-(2-Fluoro-5-(trifluoromethyl)phenyl)prop-2-enoate (37)

Yield: 0.17 g (63%) as a colorless oil; IR: 1723, 1642, 1333 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.81 (m, 1H), 7.80 (d, J = 16.2 Hz, 1H), 7.62 (m, 1H), 7.33 (t, J = 9.2 Hz, 1H), 6.60 (d, J = 16.2 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 166.2, 162.7 (d, J = 259.2 Hz), 135.5 (d, J = 2.8 Hz), 124.8 (dq, J = 9.6, 3.8 Hz), 127.3 (q, J = 33.4 Hz), 126.4 (dq, J = 7.8, 3.9 Hz), 123.5 (q, J = 271.9 Hz), 123.3 (d, J = 12.9 Hz), 122.8 (d, J = 6.4 Hz), 117.0 (d, J = 23.4 Hz), 60.9, 14.3; MS (m/z): 262 (M+); Anal. Calcd for C12H10F4O2: C, 54.97; H, 3.84; found: C, 54.99; H, 3.87.

3.12.21. Methyl 3-Hydroxy-4-(4-methylphenyl)-7-trifluoromethyl-2-naphthoate (38)

Yield: 0.34 g (90%) as an orange solid, m.p. 248–249 °C; IR: 3518, 1722, 1333, 1210, 1172 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 8.2 Hz, 2H), 7.51 (dd, J = 8.6, 2.3 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.6 Hz, 1H), 6.59 (s, 1H), 3.89 (s, 3H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 164.4, 156.1, 143.7, 136.7, 132.1, 130.4, 129.09, 129.08, 128.9 (q, J = 3.7 Hz), 125.3, 125.24 (q, J = 33.3 Hz), 125.16 (q, J = 3.8 Hz), 123.7 (q, J = 271.9 Hz), 120.1, 115.4, 108.6, 52.5, 21.3; MS (m/z): 360 (M+); Anal. Calcd for C20H15F3O3: C, 66.67; H, 4.20; found: C, 66.63; H, 4.17.

3.12.22. Methyl 3-Hydroxy-4-(4-methoxylphenyl)-7-(trifluoromethyl)-2-naphthoate (39)

Yield: 0.37 g (88%) as an orange solid, m.p. 186–187 °C; IR: 3189–2877, 2838, 1714, 1318, 1208, 1112 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.9 Hz, 2H), 7.49 (dd, J = 8.5, 2.2 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.23 (s, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 6.57 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 164.4, 158.5, 156.2, 143.0, 130.5, 129.8, 128.8 (q, J = 3.7 Hz), 127.8, 125.4, 125.2 (q, J = 33.1 Hz), 125.1 (m), 123.7 (q, J = 272.1 Hz), 120.3, 115.3, 113.8, 108.3, 55.3, 52.5; MS (m/z): 376 (M+); Anal. Calcd for C20H15F3O4: C, 63.83; H, 4.02; found: C, 63.82; H, 3.99.

3.12.23. Ethyl (E)-3-(2-Fluoropyridin-3-yl)prop-2-enoate (40)

Yield: 0.23 g (72%) as a white solid, m.p. 44–45 °C; IR: 1723, 1645, 1327, 1243 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.22 (dd, J = 4.9, 1.6 Hz, 1H), 7.95 (ddd, J = 9.4, 7.5, 1.0 Hz, 1H), 7.73 (d, J = 16.2 Hz, 1H), 7.26 (m, 1H), 6.60 (d, J = 16.2 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 166.2, 161.3 (d, J = 245.0 Hz), 148.6 (d, J = 15.4 Hz), 139.4 (d, J = 3.7 Hz), 135.6 (d, J = 3.0 Hz), 123.1 (d, J = 6.3 Hz), 121.9 (d, J = 4.5 Hz), 117.7 (d, J = 26.7 Hz), 60.9, 14.3; MS (m/z): 195 (M+); Anal. Calcd for C10H10FNO2: C, 61.53; H, 5.16; N, 7.18; found: C, 61.48; H, 5.13; N, 7.11.

3.12.24. Methyl 7-Hydroxy-8-phenylquinoline-6-carboxylate (41)

Yield: 0.39 g (88%) as an orange oil; IR: 3140–2975, 1725 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.20 (dd, J = 5.0, 2.0 Hz, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.44 (dd, J = 7.4, 1.9 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H), 7.28 (s, 1H), 7.22 (tt, J = 7.4, 1.3 Hz, 1H), 6.98 (dd, J = 7.4, 5.0 Hz, 1H), 6.64 (s, 1H), 3.90 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 164.3, 159.8, 150.0, 144.8, 136.3, 134.8, 130.8, 129.5, 128.5, 127.0, 125.4, 119.9, 115.3, 109.4, 52.5; MS (m/z): 279 (M+); Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02; found: C, 73.07; H, 4.66; N, 5.01.

3.12.25. Methyl 8-(4-Chlorophenyl)-7-hydroxyquinoline-6-carboxylate (42)

Yield: 0.43 g (86%) as an orange solid, m.p. 134–135 °C; IR: 3265–2885, 1721 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.21 (dd, J = 5.0, 1.9 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.46 (dd, J = 7.3, 1.9, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.31 (s, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.62 (s, 1H), 3.90 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 164.2, 159.6, 150.1, 145.2, 136.4, 133.3, 132.4, 131.2, 130.6, 128.6, 125.0, 120.1, 115.2, 108.1, 52.6; MS (m/z): 313, 315 (ca. 3:1, M+); Anal. Calcd for C17H12ClNO3: C, 65.08; H, 3.86; N, 4.46; found: C, 65.11; H, 3.88; N, 4.38.

3.12.26. Methyl 2-Hydroxy-8-(4-methylphenyl)quinoline-1-carboxylate (43)

Yield: 0.41 g (88%) as an orange solid, m.p. 121–122 °C; IR: 3330–2897, 1724 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.18 (dd, J = 5.0, 1.9 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.42 (dd, J = 7.3, 1.9 Hz, 1H), 7.23 (s, 1H), 7.19 (d, J = 8.2 Hz, 2H), 6.96 (dd, J = 7.3, 5.0 Hz, 1H), 6.59 (s, 1H), 3.90 (s, 3H), 2.35 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 164.4, 159.9, 149.9, 144.3, 136.9, 136.1, 131.9, 130.3, 129.4, 129.2, 125.6, 119.8, 115.4, 109.4, 52.5, 21.4; MS (m/z): 293 (M+); Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78; found: C, 73.67; H, 5.13; N, 4.75.

3.12.27. Methyl 7-Hydroxy-8-(4-methoxyphenyl)quinoline-6-carboxylate (44)

Yield: 0.42 g (84%) as an orange solid, m.p. 103–104 °C; IR: 3196–2893, 2841, 1719 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.14 (dd, J = 5.0, 1.9 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.37 (dd, J = 7.3, 1.9 Hz, 1H), 7.17 (s, 1H), 6.92 (coincident d, J = 8.8 Hz, 2H and m, 1H), 6.57 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 164.4, 159.9, 158.5, 149.7, 143.6, 136.1, 130.9, 129.8, 127.7, 123.5, 119.8, 115.5, 113.9, 109.0, 55.2, 52.5; MS (m/z): 309 (M+); Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53; found: C, 69.84; H, 4.88; N, 4.51.

4. Conclusions

In conclusion, we developed a new strategy for the synthesis of trisubstituted 2-naphthol and disubstituted 7-hydroxyquinoline derivatives. The sequence involves a reaction between 1 equiv. of an SNAr-activated 2-fluorobenzaldehyde (dielectrophile) and 2 equiv. of a 1,3-disubstituted acetone (dinucleophile). The use of 2-fluoronicotinaldehyde as the dielectrophile yields 7-hydroxyquinoline products. The transformation occurs in a single flask and requires only 2 equiv. of K2CO3 in anhydrous DMF at 65–70 °C. Thus, extensive process optimization is not required. Following mild acid workup and column chromatography, the yields are high. The reaction is regioselective with the most stable anionic center attacking the aldehyde first, followed by SNAr ring closure from the less stable anion. The current approach avoids the use of strong acids or bases under protic conditions which can attack other functionality. Additionally, expensive metal catalysts which can be difficult to remove from the final product are not required. We are continuing our work to elucidate additional [3+3] approaches to privileged ring systems important in drug synthesis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29143406/s1, Copies of 1H-NMR and 13C-NMR spectra for all cyclization products are provided.

Author Contributions

Project conception, project administration, formal analysis, and writing of the manuscript text, R.A.B.; investigation, methodology, analysis, and writing of the experimental section, K.F. and E.A. All authors have read and agreed to the published version of the manuscript.

Funding

The authors are also indebted to the OSU College of Arts and Sciences for providing funds to purchase several departmental instruments, including an FT-IR and a 400 MHz NMR unit for the Oklahoma State-wide NMR facility. The NMR facility was initially established with support from the NSF (BIR-9512269), the Oklahoma State Regents for Higher Education, the W. M. Keck Foundation, and Conoco, Inc.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

K.F. wishes to thank the OSU Foundation for a K. Darrell Berlin Fellowship in Summer 2021 and a Smith-Han Fellowship in Summer 2023; E.A. wishes to thank the OSU Foundation for K. Darrell Berlin Fellowships in Summer 2020 and 2023 as well as a Johnston Chemistry Fellowship in Summer 2021.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 03406 sch001
Scheme 1. Representative [3+3] annulation of 2-fluoro-5-nitrobenzaldehyde (dielectrophile) with dimethyl 1,3-acetonedicarboxylate (dinucleophile).
Scheme 1. Representative [3+3] annulation of 2-fluoro-5-nitrobenzaldehyde (dielectrophile) with dimethyl 1,3-acetonedicarboxylate (dinucleophile).
Molecules 29 03406 sch001
Molecules 29 03406 g001
Figure 1. Recent drug candidates incorporating 2-naphthol.
Figure 1. Recent drug candidates incorporating 2-naphthol.
Molecules 29 03406 g001
Molecules 29 03406 sch002
Scheme 2. Synthesis of hindered hydroxyaromatics via [3+3] annulation.
Scheme 2. Synthesis of hindered hydroxyaromatics via [3+3] annulation.
Molecules 29 03406 sch002
Molecules 29 03406 sch003
Scheme 3. A probable mechanism for the reaction of 1a with methyl 4-phenyl-3-oxobutanoate (8) to give 20.
Scheme 3. A probable mechanism for the reaction of 1a with methyl 4-phenyl-3-oxobutanoate (8) to give 20.
Molecules 29 03406 sch003
Molecules 29 03406 sch004
Scheme 4. Plausible mechanism for elimination from adduct of 5d with 7 to obtain cinnamic ester derivative 40. The numbers in green indicate the sequence of steps involved.
Scheme 4. Plausible mechanism for elimination from adduct of 5d with 7 to obtain cinnamic ester derivative 40. The numbers in green indicate the sequence of steps involved.
Molecules 29 03406 sch004
Table 1. 2-Naphthols from 2-fluoro-5-nitrobenzaldehyde (5a).
Table 1. 2-Naphthols from 2-fluoro-5-nitrobenzaldehyde (5a).
AldehydeDinucleophileProductYield (%)
5a
entry 1		Molecules 29 03406 i001
6		Molecules 29 03406 i002
18		89
5a
entry 2		Molecules 29 03406 i003
7		Molecules 29 03406 i004
19		88
5a
entry 3		Molecules 29 03406 i005
8		Molecules 29 03406 i006
20		89
5a
entry 4		Molecules 29 03406 i007
9		Molecules 29 03406 i008
21		93
5a
entry 5		Molecules 29 03406 i009
10		Molecules 29 03406 i010
22		94
5a
entry 6		Molecules 29 03406 i011
11		Molecules 29 03406 i012
23		91
5a
entry 7		Molecules 29 03406 i013
12		Molecules 29 03406 i014
24		96
5a
entry 8		Molecules 29 03406 i015
13		Molecules 29 03406 i016
25		85
5a
entry 9		Molecules 29 03406 i017
14		Molecules 29 03406 i018
26		96
5a
entry 10		Molecules 29 03406 i019
15		Molecules 29 03406 i020
27		87
5a
entry 11		Molecules 29 03406 i021
16		Molecules 29 03406 i022
28		89
5a
entry 12		Molecules 29 03406 i023
17 a		Molecules 29 03406 i024
29 b		82
a Decomposed with K2CO3 at 65–70 °C. b Only product when Et3N was used as base.
Table 2. 2-Naphthols from 2-fluoro-5-cyanobenzaldehyde (5b).
Table 2. 2-Naphthols from 2-fluoro-5-cyanobenzaldehyde (5b).
AldehydeDinucleophileProductYield (%)
5b
entry 1		6Molecules 29 03406 i025
30		84
5b
entry 2		8Molecules 29 03406 i026
31		83
5b
entry 3		9Molecules 29 03406 i027
32		92
5b
entry 4		10Molecules 29 03406 i028
33		92
5b
entry 5		12Molecules 29 03406 i029
34		94
5b
entry 6		14Molecules 29 03406 i030
35		95
5b
entry 7		15Molecules 29 03406 i031
36		87
Table 3. 2-Naphthols from 2-fluoro-5-(trifluoromethyl)benzaldehyde (5c).
Table 3. 2-Naphthols from 2-fluoro-5-(trifluoromethyl)benzaldehyde (5c).
AldehydeDinucleophileProductYield (%)
5c
entry 1		7Molecules 29 03406 i032
37		63
5c
entry 1		11Molecules 29 03406 i033
38		90
5c
entry 3		12Molecules 29 03406 i034
39		89
Table 4. 7-Hydroxyquinolines from 2-fluoronicotinaldehyde (5d).
Table 4. 7-Hydroxyquinolines from 2-fluoronicotinaldehyde (5d).
AldehydeDinucleophileProductYield (%)
5d
entry 1		7Molecules 29 03406 i035
40		72
5d
entry 2		8Molecules 29 03406 i036
41		90
5d
entry 3		10Molecules 29 03406 i037
42		89
5d
entry 4		11Molecules 29 03406 i038
43		90
5d
entry 5		12Molecules 29 03406 i039
44		89
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Fobi, K.; Ametsetor, E.; Bunce, R.A. A [3+3] Aldol-SNAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives. Molecules 2024, 29, 3406. https://doi.org/10.3390/molecules29143406

AMA Style

Fobi K, Ametsetor E, Bunce RA. A [3+3] Aldol-SNAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives. Molecules. 2024; 29(14):3406. https://doi.org/10.3390/molecules29143406

Chicago/Turabian Style

Fobi, Kwabena, Ebenezer Ametsetor, and Richard A. Bunce. 2024. "A [3+3] Aldol-SNAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives" Molecules 29, no. 14: 3406. https://doi.org/10.3390/molecules29143406

APA Style

Fobi, K., Ametsetor, E., & Bunce, R. A. (2024). A [3+3] Aldol-SNAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives. Molecules, 29(14), 3406. https://doi.org/10.3390/molecules29143406

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