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

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.


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)

Results and Discussion
The results of our study are summarized in Scheme 2 and Tables 1-4.The Supplementary Materials give the 1 H NMR and 13 C 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 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 (IC 50 ≤ 1.2 µM) against Hep G2 (liver), A549 (lung), MDA-231 (breast), and HeLa (cervical) cancer cell lines [25].Derivative 2 showed impressive GI 50 values at concentrations of 1.46-2.90µM 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 estrogendependent diseases such as breast cancer and endometriosis [27].Finally, structure 4 showed an IC 50 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].
Molecules 2024, 29, x FOR PEER REVIEW 2 of 17 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-SNArdehydration sequence (see Scheme 1).This provides a straightforward synthesis of 2naphthols 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 1.46-2.90μM 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].

Results and Discussion
The results of our study are summarized in Scheme 2 and Tables 1-4.The Supplementary Materials give the 1 H NMR and 13 C 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

Results and Discussion
The results of our study are summarized in Scheme 2 and Tables 1-4.The Supplementary Materials give the 1 H NMR and 13 C 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 K 2 CO 3 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 (NO 2 , CN) and inductively withdrawing (CF 3 ) 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.
Molecules 2024, 29, x FOR PEER REVIEW 3 of 17 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.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.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.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.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.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.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.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.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 pro- 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)(9)(10)(11)(12)(13)(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-2one [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 S N Ar ring closure [33].The process was promoted by K 2 CO 3 ; 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 S N Ar 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 S N Ar 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.
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. 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.
Finally, two examples involving reactions of the less-activated S N Ar acceptors 5c and 5d with diethyl 1,3-acetonedicarboxylate (7) underwent elimination reactions to afford cinnamate ester products rather than the expected S N Ar cyclization to produce 2-naphthol 37 and 7-hydroxyquinoline 40, respectively (entry 1 in Tables 3 and 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.substituted substrate 5b.Dielectrophiles 5-trifluoromethyl-2-fluorobenzaldehyde (5c) an 2-fluoronicotinaldehyde (5d) were less reactive but also afforded annulation produc with several of the dinucleophiles.Only one dinucleophile, 1,3-bis(phenylsulfonyl)pr pan-2-one (17), failed to give a [3+3] product in the nitro series (Table 1, entry 12).For th 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 resulte in the degradation of 17 but led to a respectable yield (82%) of 5-nitro-(phenylsulfonyl)benzaldehyde (29).The confirmation of the identity of 29 was accom plished by comparison with the same compound prepared from 2-fluoro-5-nitrobenza dehyde and 2 equiv. of sodium benzenesulfinate in DMF containing 2 equiv. of Et3N 65-70 °C for 30 min.
Finally, two examples involving reactions of the less-activated SNAr acceptors 5c an 5d with diethyl 1,3-acetonedicarboxylate (7) underwent elimination reactions to affor cinnamate ester products rather than the expected SNAr cyclization to produce 2-naphth 37 and 7-hydroxyquinoline 40, respectively (entry 1 in Tables 3 and 4).In these transfo mations, one can envision a base-initiated Grob-type fragmentation [34] (Scheme 4) wi the loss of a malonate fragment in addition to hydroxide.The antiperiplanar alignment these groups should facilitate this elimination to the stable conjugated ester product.

General Methods
Unless otherwise indicated, all reactions were performed under dry N2 in dry glas ware.All commercial reagents and solvents were used as received (Combi Blocks, Sa Diego, CA, USA and Fisher Scientific, Pittsburgh, PA, USA).All wash solutions employe in work-up procedures were aqueous.Reactions were followed by thin layer chromato raphy on Analtech No 21521 silica gel GF plates (Newark, DE, USA).Preparative separ tions were accomplished by column chromatography on Davisil ® , grade 62, 60-200-mes silica gel containing 0.5% of UV-05 phosphor (both from Sorbent Technologies, Norcros GA, USA) slurry packed into quartz columns.Band elution for all chromatographic sep rations was monitored using a hand-held ultraviolet lamp (Fisher Scientific, Pittsburg PA, USA).Melting points (uncorrected) were obtained using a MEL-TEMP apparatu (Cambridge, MA, USA).FT-IR spectra were run as thin films on sodium chloride disks in ATR mode using a Nicolet iS50 spectrophotometer (Madison WI, USA). 1 H-and 13 C NMR spectra were obtained using a Bruker Avance 400 system (Billerica, MA, USA) at 40 MHz and 101 MHz, respectively, in CDCl3 or DMSO-d6 containing 0.05% tetram thylsilane as the internal standard (Cambridge Isotope Laboratories, Andover, MA, USA Chemical shifts are given in ppm downfield from the internal standard, and coupling co stants (J) are reported in Hz.Low-resolution mass spectra were obtained using a Hewle 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.

General Methods
Unless otherwise indicated, all reactions were performed under dry N 2 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). 1 H-and 13 C-NMR spectra were obtained using a Bruker Avance 400 system (Billerica, MA, USA) at 400 MHz and 101 MHz, respectively, in CDCl 3 or DMSO-d 6 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.

29 ba
Decomposed with K 2 CO 3 at 65-70 • C. b Only product when Et 3 N was used as base.

Scheme 4 .
Scheme 4. Plausible mechanism for elimination from adduct of 5d with 7 to obtain cinnamic est derivative 40.The numbers in green indicate the sequence of steps involved.