key: cord-0888910-zepap447
authors: Belyaeva, Kseniya V.; Nikitina, Lina P.; Afonin, Andrei V.; Trofimov, Boris A.
title: Acylacetylenes in multiple functionalization of hydroxyquinolines and quinolones
date: 2020-08-20
journal: Tetrahedron
DOI: 10.1016/j.tet.2020.131523
sha: 97cbd7e4ba1739d124d7372002b12f1248781d6f
doc_id: 888910
cord_uid: zepap447

The expected one-pot multiple functionalization of hydroxyquinolines and quinolones with acylacetylenes (20 mol% KOH, 5 equiv. H(2)O, MeCN, 55–60 °C), which, according to the previous finding, might involve the addition of OH and NH-functions to the triple bond and insertion of acylacetylenes into the quinoline scaffold, retains mainly on the formation of chalcone-quinoline ensembles in up 99% yield. The higher functionalized quinolines can be obtained in a synthetically acceptable yield, when the above ensembles are treated with the second molecule of acylacetylenes. Thus, the further insertion of second molecule of the acetylenes into the quinoline scaffold occurs as a much slower process indicating a strong adverse substituent effect of the remote chalcone moiety.

Functionalized quinoline scaffold is a frequently met structural motif in a plethora of biologically important compounds, both of natural and synthetic origin. The wide spectrum of their biological activity covers anti-cancer, 1,2 antibacteria l-5 antioxidant, 1 and antifungal. 6 Functionalized quinolines 7, 8 and fluoroquinolines [9] [10] [11] [12] [13] [14] gave rise to a new generation of antibiotics. The modern antimalarial therapy cannot be imaged without the functionalized natural quinoline, quinine, and its later modifications such as chloroquine, amodiaquine, and mefloquine [15] [16] [17] ( Figure 1 ). The latter is now considered as a possible drug against coronavirus COVID-19. 18 Therefore, further modifications of the quinine structure can be rated as requested by time. In this context, the recent modification of the quinine with acylacetylenes 19 (Scheme 1) looks timely.

When choosing the latter, we were guided by the following reasons: (i) the ability of the acylacetylenes to generate chalcone upon adding protogenic (OH or NH) functions to the triple bond; (ii) potential biological activity of the aromatic (aryl) or heteroaromatic (pyrrolyl, furyl, thienyl) substituents; (iii) synthetically suitable balance between high reactivity and stability (convenience to be handled). The merging of biological active chalcone [30] [31] [32] and quinoline [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] structures in a one molecule could result in a synergetic effect and extension of the scope of their pharmaceutically important properties. The acetylenic ketone with branched acetal substituents at the triple bond 2i, benzoyloxysecbutylbenzoylacetylene, was specially synthesized to provide additional possibilities for further functionalization (in particular, after deprotection of the hydroxyl group) of adducts as well as to evaluation steric effect of the reaction.

To verify the possibility of the above hypotized triple functionalization of hydroxyquinolines with acylacetylenes the reference reaction between 6-hydroxyquinoline 1b and benzoylphenylacetylene 2a under the optimum conditions (Scheme 2) has been tested. Disappointingly, the results did not entirely meet the expectations: mainly only nucleophilic addition of the hydroxyl group to the triple bond (even with two-fold excess of the ketone) occurred to afford benzoyl-1-phenyl-ethenyloxyquinoline 3b, no signs of 2,3-difunctionalization of the quinoline ring were observed. The expected product of triple functionalization 4b was detectable ( 1 H NMR) in the crude as a minor product in amount of ~ 9% (Scheme 3). Notably, as previously shown, 29 6-methoxyquinoline, when reacted with ketone 2a under the same conditions, readily underwent the insertion of the ketone moiety into the quinoline ring to deliver 2-phenyl-3-benzoyl-6-methoxyquinoline in 62% yield. Since 2,3-difunctionalization starts with the formation of donor-acceptor adduct (zwitterion) between nitrogen atom and electron-deficient acetylene, 29 obviously, here we face extraordinary long-range transmittance of electron-withdrawing effect of the carbonyl group over the nitrogen atom through the whole quinoline ring system. Eventually, we have managed to render the above triple functionalization of quinoline scaffold in a stepwise manner and synthesized trifunctionalized product 4b in modest 24% yield when preliminary prepared adduct 3b was treated with ketone 2a (Scheme 4) under the same conditions of Scheme 3. Thus, we have been edged to focus our study on optimization of the synthesis of monofunctionalized quinoline 3b. The selected experimental results illustrating the yield/reaction condition relationship are presented in Table 1 . The reaction was carried out at the equimolar ratio of the reactants, the variable parameters being the nature and concentration of a catalyst (inorganic or organic base), the content of water, and temperature. The process duration was determined by the full consumption of the acetylenic ketone 2a or by the moment when its concentration stopped changing. The progress of the reaction was monitored using the IR spectroscopy to follow the disappearance of the absorption band (С≡С bond) of acetylene 2а at 2198 cm -1 .

As anticipated, the reaction did not take place without the base catalyst (entry 1). The best result (92% yield of 3b, 70% of the (Z)-stereoselectivity, entry 4) was attained under the following conditions: 20 mol% KOH, 5 equiv. of water, MeCN, 55-60 o C, 0.5 h). The yield of the target product mostly depends on the nature of a basic catalyst being highest with KOH and being dropped in the order KOH > K 2 CO 3 > DBU > NaOH > Ph 3 P > K 3 PO 4 > Et 3 N. A lesser influence on the product yield and the reaction time was observed for concentration of KOH (entries 3, 4, 5) and water (entries 6, 7). A higher concentration of KOH likely facilitates the side base-catalyzed hydration of the acetylenic ketone. The presence of water had a slightly favorable effect on the yield of the target product and the reaction stereochemistry. Apparently, water molecules participate as a proton transfer agents in the reaction transition state as it commonly accepted for nucleophilic addition to acetylenes. 33 Consequently, such reactions are stereoselective leading to the (Z)-isomers exclusively. A partial deviation from this rule in this case is likely due to steric encumbrance in the Z-isomer of 3b (benzoyl and quinolynyl oxy moiety located on the same side of the double bond).

An advantageous feature of the reaction is that it can be efficiently realized at room temperature (entry 9) albeit in this case it lasted much longer (48 h) and to complete it for 30 min it required 55-60 o C (entry 4).

Basing on the data of Table 1 , to evaluate the scope of monofunctionalization of quinolines 1a-c with acylacetylenes 2a-i we taken the conditions, which were found to be best (20 mol% of KOH, 5 equiv. of water, 55-60 o C), the process time being dependent on the reaction completion (Scheme 5). As follows from Scheme 5, the reaction well tolerates 3-, 6-and 8-hydroxyquinolines 1ac and all the abovementioned series of acylacetylenes 2a-i. The process proceeded smoothly for a short time (15 min-2 h) to provide the target functionalized quinolines 3a-m, mostly in goodto-excellent yields. As far as the product yields do not differ considerably, the substituent effect can be roughly estimated from the reaction time. Using this criterion, the reactivity of hydroxyquinolines under question may be ordered as follows: 1b (6-OH) > 1c (8-OH) > 1a (3-OH) that approximately reflects nucleophilicity of the corresponding O-centered anions. The effect of substituents in the acylacetylenes is generally in consistence with character of the reaction as a nucleophilic addition to the triple bond. Indeed, electron-donating groups such as tolyl, pyrrolyl which reduce electrophilicity of the triple bond expectedly slow down the reaction rate (compounds 3j-l). On the contrary in case of nitrobenzoyl substituent (compound 3e), the syntheses completed faster. Comparatively low yield of the target product in this case (79%) is due to side base-catalyzed hydration of the triple bond, as previously observed. 29 Noteworthy that with benzoyl-(5-arylpyrrol-2-yl)acetylenes 2g,h, it was required to increase the alkali loading (up to 1.2 equiv.), since ~ 1 equivalent of the base was spent for the pyrrolate formation.

In this case of compounds 3k,l, the intramolecular N−H···O=C hydrogen bond is formed between hydrogen of the NH group and oxygen of the carbonyl group ( Figure 3 ). This is manifested by an extraordinary downfield shift (to 14.8 ppm) of the NH group hydrogen signal (vs 9.25 ppm). Therefore, compounds 3k,l adopts only the (E)-configuration stabilized by the intramolecular hydrogen bond. The chemical shift of the β-hydrogen of the olefin fragment (δH β ) in the (E)-isomers of 3k,l is 6.27 ppm. Basing on this, the isomers of the compounds 3a-m, where the δH β value is within the range from 6.0 to 6.2 ppm, are assigned to the (E)configuration, while the isomers of the compounds 3a-m, where the δH β value ranges from 7.0 to 7.2 ppm, are assigned to the (Z)-configuration. At the same time the β-hydrogen signals of both isomers of the compound 3m are shifted upfield by 0.3-0.5 ppm since no influence of the anisotropy of the phenyl ring takes place in this case. Quinolines functionalized at the 2-and 4-position by a hydroxyl group are known to exist predominantly in the keto form, [34] [35] [36] [37] i.e. as 2-and 4-quinolones 1d-f, respectively. Consequently, they reacted under the above conditions mostly as N-centered nucleophiles to deliver the hybrid molecules 5a-d, which combine the quinoline and enaminone entities (Scheme 7). The products yields were excellent ranging 85-95%. As anticipated, the reaction was regioselective. In this case products were obtained predominantly as (Z)-isomers.

For the series of N-adducts 5a-d, only compound 5b was obtained as two isomers in which the β-hydrogen signals appear at 7.0 and 7.6 ppm. Based on the previous consideration, the isomer of 5b, where the δH β value is 7.0 ppm, is assigned to the (E)-configuration, whereas the isomer of 5b, where the δH β value is 7.6 ppm, is assigned to the (Z)-configuration. In addition, since the signal of the β-hydrogen of the olefin fragment resonates at 7.6-8.0 ppm in compounds (5a,c,d), their isomers are assigned to the (Z)-configuration.

The possibility of the further functionalization of the obtained products was exemplified by the reduction (NaBH 4 ) of adduct 3b to afford the allylic alcohol 6b (Scheme 8).

There are two characteristic pairs of the upfield doublets (5.76; 6.18 and 5.48; 5.60 ppm, respectively) splitting due to the vicinal spin-spin coupling ( 3 J H,H = 8.8 and 9.9 Hz, respectively) in the 1 H NMR spectrum of the (Z)-and (E)-isomers as well as a broad absorption bond at 3200 cm -1 in the IR spectrum of compound 6b.

In conclusion, the base-catalyzed reaction of acylacetylenes with hydroxyquinolines and quinolone gives rise to new representatives of highly functionalized quinolines containing chalcone and enaminone moieties in good to excellent yields. The triple functionalization by insertion of second molecule of acylacetylenes into the position 2 and 3 of quinoline scaffold, previously observed under the same conditions, occurs as a slower process than likely results from a long-range transmittance of the electron-acceptor effect of the chalcone substituent on quinoline nitrogen. The combination of biologically active entities such as quinoline ring and chalcone or enaminone fragment in a one molecule may be of interest in the synthesized compounds from specialists of bio-and medical chemistry.

Quinolines 1a-f and solvents were purchased from commercial sources and used without further purification. Samples of acylacetylenes 2a-f,i 38 and 2g,h, 39 were obtained according to describe methods. Monitoring of the reaction was carried out using the method of IR spectroscopy to follow the disappearance of the C≡C bond intensity of acetylenes 2 at 2195-2264 cm -1 . The products 3a-m, 4b, 5a-d and 6b were separated and purified by column chromatography on silica gel (0.06-0.2 mm) with chloroform/toluene/ethanol (20:4:1) mixture as eluent. NMR spectra were recorded on a Bruker DPX-400 spectrometer (400.1 MHz for 1 H and 100.6 MHz for 13 C) in CDCl 3 . The internal standards were HMDS (for 1 H) or the residual solvent signals (for 13 C). IR spectra were obtained with a Bruker Vertex 70 spectrometer (400-4000 cm -1 , microlayer). Mass spectra were recorded on Mass spectrometer HR-TOF-ESI-MS Agilent 6210 (USA) in the mode of recording positive results with acetonitrile as solvent and 0.1% perfluorobutyric acid as ionizing agent. Melting point (uncorrected) was determined on a Kofler micro hot stage apparatus.

A mixture of hydroxyquinoline 1 (0.5 mmol), acylacetylene 2 (0.5 mmol), KOH (20 mol%), H 2 O (2.5 mmol) in acetonitrile (0.5 mL) was placed in a 10-mL round-bottom flask (air atmosphere) with stir bar and stirred at 55-60 о С for appropriate time. After the reaction completion the reaction mixture cooled, solvents were evaporated at a low pressure and the residue was passed through the chromatography column deliver to the target product 3 or 5.

Following the general procedure, 3a was prepared from 3-hydroxyquinoline 1a (73 mg, 0.5 mmol) and acetylene 2a (103 mg, 0.5 mmol); 3a was isolated as a dark-yellow oil (151 mg, 86 % yield). 

Following the general procedure, 3b was prepared from 6-hydroxyquinoline 1b (73 mg, 0.5 mmol) and acetylene 2a (103 mg, 0.5 mmol); 3b was isolated as a brown oil (162 mg, 92% yield). 

Following the general procedure, 3c was prepared from 8-hydroxyquinoline 1c (73 mg, 0.5 mmol) and acetylene 2a (103 mg, 0.5 mmol); 3c was isolated as an yellow oil (165 mg, 94 % yield). 

Following the general procedure, 3d was prepared from 6-hydroxyquinoline 1b (73 mg, 0.5 mmol) and acetylene 2b (118 mg, 0.5 mmol); 3d was isolated as a brown oil (184 mg, 96% yield). 

Following the general procedure, 3e was prepared from 6-hydroxyquinoline 1b (73 mg, 0.5 mmol) and acetylene 2c (126 mg, 0.5 mmol); 3e was isolated as a dark-yellow powder (157 mg, 79% yield), mp 148-150 o C (EtOH). 1-(2-Furyl)-3-phenyl-3-(quinolin-3-yloxy) prop-2-en-1-one (3f) Following the general procedure, 3f was prepared from 3-hydroxyquinoline 1a (73 mg, 0.5 mmol) and acetylene 2d (98 mg, 0.5 mmol); 3f was isolated as an yellow oil (166 mg, 97% yield). 

Following the general procedure, 3j was prepared from 6-hydroxyquinoline 1b (73 mg, 0.5 mmol) and acetylene 2f (110 mg, 0.5 mmol); 3j was isolated as a brown oil (180 mg, 99% yield). E:Z-isomer ratio 20:80 ( 1 H NMR); (Z)-isomer 1 

HRMS (ESI): m/z calcd for C 25 H 20 NO 2 +

-phenyl-1H-pyrrol-2-yl)-3-(quinolin-6-yloxy)prop-2-en-1-one (3k) Following the general procedure

27 (s, 1H, H β ); 13 C NMR (101 MHz

HRMS (ESI): m/z calcd for C 28 H 21 N 2 O 2 +

-Fluorophenyl)-1H-pyrrol-2-yl)-1-phenyl-3-(quinolin-6-yloxy)prop-2-en-1-one (3l) Following the general procedure

In this case 1.2 equivalents of KOH were used. 3l was isolated as a brown oil (152 mg, 70% yield). 1 H NMR (400 MHz

7.74 (m, 1H, H-6 from 3-FC 6 H 4 ), 7.27 (m, 1H, H-3), 7.35-7.25 (m, 4H, H-5 from 3-FC 6 H 4 and H m,p from Bz), 7.10 (m, 1H, H-3' from pyrrolyl), 6.97 (m, 1H, H-4 from 3-FC 6 H 4 ), 6.72 (m, 1H, H-4' from pyrrolyl)

C-8a), 140.2 (C-5' from pyrrolyl), 136.1 (C i from Bz)

C-8), 130.8 (d, 3 J CF = 8.0 Hz, C-5 from 3-FC 6 H 4 )

6 (d, 2 J CF = 21.0 Hz, C-2 from 3-FC 6 H 4 ), 111.7 (d, 2 J CF = 23.0 Hz, C-4 from 3-FC 6 H 4 )

IR (microlayer): 1625 (C=O), 1616, 1578 (C=C) cm -1

HRMS (ESI): m/z calcd for C 28 H 20 FN 2 O 2 +

Following the general procedure, 3m was prepared from 6-hydroxyquinoline 1b (73 mg, 0.5 mmol) and acetylene 2i (153 mg, 0.5 mmol); 3m was isolated as an yellow oil (166 mg, 74% yield). E:Z-isomer ratio 65:35 ( 1 H NMR); (Z)-isomer 1 H NMR (400 MHz

Me) = 8.0 Hz, 2H, CH 2 )

C-2), 144.8 (C-8a), 138.1 (C i' from Ph), 135.1 (C-4)

Hz, 1H, H-4), 7.94 (m, 2H, H o' from Ph), 7.82 (m, 1H, H p from Ph), 7.65 (m, 2H, H o from Ph)

CDCl 3 ): δ = 191.3 (C=O)

IR (microlayer): 1716, 1661 (C=O), 1602 (C=C) cm -1

HRMS (ESI): m/z calcd for C 29 H 26 NO 4 +

Following the general procedure, 5a was prepared from 4-methylquinolin-2(1H)-one 1d (81 mg, 0.5 mmol) and acetylene 2a (103 mg, 0.5 mmol); 5a was isolated as a light-yellow powder (156 mg, 85% yield), mp 209-211 o C (EtOH). 1 H NMR (400 MHz

C-4), 139.6 (C-8a), 138.2 (C i' from Ph)

IR (microlayer): 1662 (C=O), 1597 (C=C) cm -1

HRMS (ESI): m/z calcd for C 25 H 20 NO 2 +

mmol) and acetylene 2a (103 mg, 0.5 mmol); 5b was isolated as an yellow powder (157 mg, 89% yield

60 (s, 1H, H β

C-4), 149.2 (C α ), 142.6 (C-2)

CDCl 3 ): δ = 8.42 (d, 3 J 5,6 = 7.6 Hz, 1H, H-5), 7.97 (m, 2H, H o' from Ph), 7.73 (d, 3 J 7,8 = 7.8 Hz

CDCl 3 ): δ = 191.5 (C=O), 178.5 (C-4), 149.8 (C α ), 142.5 (C-2), 140.4 (C-8a), 137.5 (C i' from Ph)

IR (microlayer): 1662, 1624 (C=O), 1603 (C=C) cm -1

HRMS (ESI): m/z calcd for C 24 H 18 NO 2 +

Methylquinolin-4-yl)oxy]-1,3-diphenylprop-2-en-1-one (5c) Following the general procedure, 5c was prepared from 2-methylquinolin-4(1H)-one 1f (81 mg, 0.5 mmol) and acetylene 2a (103 mg, 0.5 mmol); 5c was isolated as an yellow powder (174 mg, 95% yield), mp 218-220 o C (EtOH). 1 H NMR (400 MHz

33 (s, 1H, H-3), 2.22 (s, 3H, Me); 13 C NMR (101 MHz

IR (microlayer): 1664, 1623 (C=O), 1610 (C=C) cm -1

HRMS (ESI): m/z calcd for C 25 H 20 NO 2 +

(Z)-1-(2-Furyl)-3-phenyl-3-(quinolin-4-yloxy)prop-2-en-1-one (5d) Following the general procedure

mmol) and acetylene 2d (98 mg, 0.5 mmol); 5d was isolated as an yellow powder (148 mg, 87% yield), mp 206-207 o C (EtOH). 1 H NMR (400 MHz, CDCl 3 ): δ = 8.31 (d, 3 J 5,6 = 8.0 Hz, 1H, H-5), 7.59 (s, 1H, H β ), 7.49 (m, 1H, H-5'), 7.37 (m, 4H, H o,m from Ph), 7.33 (m, 2H, H-7, H-8), 7.27 (m, 1H, H-6), 7.17 (m, 1H, H p from Ph), 7.15 (m, 1H

IR (microlayer): 1657, 1623 (C=O), 1602 (C=C) cm -1

HRMS (ESI): m/z calcd for C 22 H 16 NO 3 +

-benzoyl-2-phenylquinolin-6-yl)oxy)-1,3-diphenylprop-2-en-1-one (4b) A mixture of benzoylphenyl-ethenyloxyquinoline 3b (202 mg, 0.58 mmol), acetylene 2a (119 mg, 0.58 mmol), KOH (6 mg, 20 mol%), H 2 O (574 mg, 32 mmol) and acetonitrile (1 mL) was placed in a 10-mL round-bottom flask (air atmosphere) with stir bar and stirred at 55-60 о С for 48 h. Then the reaction mixture was cooled

isomer 1 H NMR (CDCl 3 ): δ = 8.11 (d, 3 J 7,8 = 8.0 Hz, 1H, H-8), 8.05 (s, 1H, H-4), 7.90 (m, 2H, H o from C β -Bz), 7.73 (m, 2H, H o from C α -Ph), 7.63

C-2, C-6), 145.0 (C-8a), 139.7 [C i from C(2)-Ph], 138.6 (C i from C β -Bz), 137.0 [C i from C(3)-Bz], 136.6 (C-4), 134.2 (C i from C α -Ph)

28 (s, 1H, H β ), other signals are overlapped with major isomer

IR (microlayer): 1663 (C=O), 1595 (C=C) cm -1

Procedure for synthesis of 1,3-diphenyl-3-(quinolin-6-yloxy)prop-2-en-1-ol (6b) A solution of benzoylphenylethenyloxyquinoline 3b (170 mg, 0.48 mmol), NaBH 4 (90 mg, 2.40 mmol) in 1 mL of EtOH was placed in a 10-mL round-bottom flask (air atmosphere) with stir bar and stirred at 20-25 о С for 4 h. Then the reaction mixture was concentrated under the low pressure, dissolved with Et 2 O (2 mL) and washed with H 2 O (3 × 1 mL). Organic layer was dried under MgSO 4 , filtered and concentrated in vacuo. The crude mixture was purified via silica

isomer 1 H NMR (400 MHz, CDCl 3 ): δ = 8.57 (m, 1H, H-2), 7.91 (d, 3 J 7,8 = 7.6 Hz, 1H, H-8), 7.74 (d, 3 J 3,4 = 7.6 Hz, 1H, H-8), 7.49 (m, 2H, H o from C γ -Ph), 7.40-7.20 (m, 10H, H-3, H-7, H o,m,p from Ph, H m,p from C γ -Ph), 7.03 (s, 1H, H-5)

Other signals in 1 H NMR were overlapped with signals of major isomer

HRMS (ESI): m/z calcd for C 24 H 20 NO 2 +

Pharmaceutical substances (syntheses, patents, applications)

ACS Symposium Series 1003

Fluorine in Heterocyclic Chemistry

Targets in Heterocyclic Systems

The authors declare that they have no known competingfinancial interests or personal relationships that could haveappeared to influence the work reported in this paper.

The spectral data were obtained using the equipment of Baikal Analytical Center for collective use of Siberian Branch of the Russian Academy of Sciences. ESI-HRMS spectra were obtained at Shared Research Facilities for Physical and Chemical Ultramicroanalysis LIN SB RAS.

Supplementary data to this article can be found online at…