Synthesis of Quinolines and Isoquinolines via Site-Selective, Domino

Jun 14, 2019 - As part of our ongoing interest(10) in harnessing ynone chemistry for .... by harnessing the proclivity of nitromethane as a recursive ...
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Cite This: J. Org. Chem. 2019, 84, 8731−8742

Synthesis of Quinolines and Isoquinolines via Site-Selective, Domino Benzannulation of 2- and 3‑Chloropyridyl Ynones with Nitromethane Mallesh Beesu and Goverdhan Mehta* School of Chemistry, University of Hyderabad, Hyderabad 500 046, India

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ABSTRACT: An approach of general applicability to diverse quinolines and isoquinolines via a tactic that utilizes the recursive anion from nitromethane as a 1C-connector to stitch easily and appropriately crafted pyridyl ynones through a transition-metal-free, tandem Michael addition−SNAr process is delineated. The straightforwardness, one-pot operation, and good yields mark this methodology for wider exploitation in targeting more embellished quinolines and isoquinolines and complex platforms embodying these moieties.

Q

reactions like the Skarup synthesis, Doebner−Miller reaction, and Friedländer synthesis for quinolines and Bischler− Napieralski and Pictet−Spengler reactions for isoquinolines, which are among the classics that every learner of organic synthesis is familiar with.7 In recent decades, approaches based on metal-mediated cyclizations, couplings, and intramolecular or multicomponent variants have been explored more and are on ascendency. At a conceptual level, most of the approaches to quinolines and isoquinolines are based on pyrido-annulation of appropriately functionalized aryl derivatives with the generation of the heterocyclic ring.8 On the other hand, a conceptually contrasting “back-to-the-front” approach toward quinolines and isoquinolines involving benzannulation of substituted pyridines has received only limited attention. There have been a few sporadic efforts in this direction and are captured in Scheme 1.9 These examples, though useful, sometime require recourse to expensive catalysts (Ag, Au, Pd, Zr/Cu), and the preparation of the precursor pyridine platforms for executing benzannulation entails considerable effort. However, given the ready and affordable access to a sizable pyridine bank, there is need to develop new approaches that utilize this resource through simple, concise benzannulation protocols, which would constitute an attractive entry into variously substituted quinolines and isoquinolines.6−9 As part of our ongoing interest10 in harnessing ynone chemistry for developing new methodologies for the construction of polycyclic aromatics, we have recently demonstrated a one-pot, transition-metal-free, domino Michael−SNAr approach to polyfunctional naphthalenes10c via benzannulation of o-bromo-arylynones (acting as a dual acceptor for a tandem Michael addition and SNAr substitution)

uinoline and isoquinoline frameworks are among the more familiar, widely accessed, and extensively investigated heterocyclic ring systems. A range of bioactive natural products, clinically used drugs and pharmaceuticals, and new materials for optoelectronic applications are either based entirely on functionally embellished quinoline and isoquinoline platforms or embody these motifs as a part of their complex molecular architecture.1 For example, the classical antimalarial natural product quinine (1), very recently introduced single dose synthetic antimalarial drug tafenoquine (2) and its earlier classical variant primaquine (3), antiasthmatic drug montelukast (4), topoisomerase inhibitor anticancer natural product camptothecin (5), and moldderived antibiotic lavendamycin (6) are representative examples of quinoline-based drugs and natural products (Figure 1).2 In addition to their utility and presence in many clinically used drugs spanning diverse therapeutic domains, quinoline-based polymers find applications in the field of electronics, optoelectronics, and nonlinear optics3 and its derivatives are also used in organocatalysis and asymmetric synthesis.4 An isoquinoline motif, being a regioisomeric sibling of quinoline, is present among one of the largest group of bioactive natural products, commonly recognized as “isoquinoline alkaloids”. Notable examples in this group are of classical natural products like the antispasmodic drug papaverine (7), emetine (8), berberine (9), complex anticancer drug ecteinascidin 743 (10), potent anticancer compound pancratistatin (11), and antitumor carbazole-isoquinoline hybrid lansine F (12) (Figure 2).5 Additionally, synthetic compounds and complexes based on an isoquinoline framework have been investigated as new drug leads and advanced materials.1 Given their importance and widespread interest in various counts (vide supra), numerous synthetic routes toward quinolines and isoquinolines have been devised that date back to over a century.6 Many of these are celebrated name © 2019 American Chemical Society

Received: April 6, 2019 Published: June 14, 2019 8731

DOI: 10.1021/acs.joc.9b00950 J. Org. Chem. 2019, 84, 8731−8742

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The Journal of Organic Chemistry

Figure 1. Representative examples of quinoline-based bioactive natural products and synthetic compounds

Figure 2. Notable examples of isoquinoline-based biologically active natural products.

see Table S1]; the reaction afforded 8-nitro-7-phenylquinolin5-ol (16a) in 80% yield (Scheme 3). When this reaction was performed under ambient conditions, only Michael addition product 18 was isolated (75%), which upon additional exposure to NaOMe (1.0 equiv) at 80 °C led to 16a in 78% yield (Scheme 3), thus lending credence to our mechanistic proposal of a two step Michael−SNAr mechanism for quinoline formation. Indeed, this reaction appeared scalable, and as a demonstrator, 16a was easily prepared on a gram scale, enabling exploration of potentially useful transformations as shown in Schemes 4 and 5. Trifluoromethanesulfonate 19 from 16a readily undergoes Suzuki and Sonogashira coupling with phenylboronic acid and phenylacetylene under standard conditions to furnish 8-nitro-6,7-diphenylquinoline (20) and 8-nitro-7-phenyl-5-(phenylethynyl)quinoline (21), respectively (Scheme 4). The methoxy quinoline compound 22 derived from 16a could be regioselectively brominated with NBS to furnish 3,6dibromoquinoline 23 (Scheme 5), which on stepwise, selective Suzuki coupling sequentially furnished 24 with phenlboronic acid and further with tolylboronic acid coupling led to 25. Thus, a flexible and uncommon 5,6,7,8-tetrasubstition pattern on quinoline could be readily installed. Lastly, the presence of the C8 nitro group in 22 was harnessed by transforming it to

mediated by nitromethane (13) (one-carbon source and a dual donor for tandem Michael addition−SNAr substitution). Extending the synthetic potential of this recently unveiled the benzannulation strategy to ynones appended to heterocyclic platforms held considerable promise to access diverse polycyclic heteroaromatics, particularly from simpler, abundantly available heterocycles. For example, implementation of this theme on easily accessed and appropriately crafted pyridyl ynones should lead to site-selective benzannulation to eventuate in either quinolines or isoquinolines through the tandem Michael addition−SNAr process as indicated in Scheme 2. An efficient and successful realization of this objective, culminating in a new general synthesis of polyfunctional quinolines and isoquinolines from substituted o-chloropridyl ynones involving benzoannulation mediated by nitromethane through domino/tandem Michael−SNAr steps, is disclosed in this report. Notably, this approach employs benchtop building blocks and reagents and involves operationally simple, routine procedures (metal-free, one-pot reaction). To implement the conceptual framework depicted in Scheme 2, the reaction between a model 2-chloroaryl ynone [1-(2-chloropyridin-3-yl)-3-phenylprop-2-yn-1-one (14a)] and nitromethane (13) was performed. Several bases like NaOMe, K2CO3, Cs2CO3, and DBU were explored but under optimized reaction conditions [NaOMe (3.0 equiv), MeOH, 80 °C, 6 h; 8732

DOI: 10.1021/acs.joc.9b00950 J. Org. Chem. 2019, 84, 8731−8742

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The Journal of Organic Chemistry Scheme 1. Recent Examples of Quinoline and/or Isoquinoline Syntheses via Benzannulation of Pyridines

assembled from commercial 2-chloronicotinic acid via its acid chloride and Sonogashira coupling with the appropriate alkyne and having diverse substitutions (aryl, naphthyl, and alkyl) on the ynone triple bond, were investigated to deliver the corresponding functionalized quinolines 16a−r in consistent decent yields, Scheme 6. The structural integrity of the quinoline products was established through the internally consistent spectral data and single-crystal X-ray structure determination of 16g, Scheme 6. A plausible reaction mechanism for the new domino process is shown in Scheme 7. An initial Michael addition of the nitromethane anion to 14a leads to the intermediate 27a, which tautomerizes to the enone 27b (isolated and characterized). The recursive carbanion generated from 27b then displaces the aromatic chloride in a SNAr fashion to deliver 27c followed by aromatization to deliver 16a, Scheme 7. A 6-π electrocyclization/halogen elimination process on the dienolate derived from 27b, leading to 16a, can also be invoked but is less likely in view of the well-documented propensity of 2-halopyridines toward the SNAr reaction. In the back drop of this new quinoline synthesis, it was pertinent to ask whether, by reshuffling the ynone and halogen substituents on the pyridine ring, it will be possible to access isoquinolines through an identical reaction course. Indeed, this turned out to be so and employing 3-chloropyridyl ynones (assembled from commercial 3-chloro-isonicotinic acid through Sonogashira coupling with the corresponding alkyne through an adaptation of precedented literature steps, vide

Scheme 2. Conceptualization of a New Strategy Toward Quinolines and Isoquinolines

Scheme 3. Initial Synthesis and Control Experimentsa

Reaction conditions: (i) CH3NO2 (13), NaOMe, 80 °C, 6 h; (ii) CH3NO2, NaOMe, rt, 6 h; (iii) NaOMe, 80 °C, 6 h.

a

the new pyridocarbazole framework 26 via Cadogan cyclization (Scheme 5).11 With this ready access to quinoline 16a and its utilitarian prospects, it was of interest to demonstrate the generality of the domino Michael−SNAr reaction through the reaction between diverse 2-chloropyridyl ynones and nitromethane (13). In all, 18 2-chloropyridyl ynones 14a−r, readily 8733

DOI: 10.1021/acs.joc.9b00950 J. Org. Chem. 2019, 84, 8731−8742

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The Journal of Organic Chemistry Scheme 4. Selected Functional Group Transformations on Model Quinoline 16aa

a Reaction conditions: (i) Tf2O, pyridine, CH2Cl2, rt, 12 h; (ii) PhB(OH)2, K2CO3, Pd(PPh3)4, PhCH3/water (1:1), 100 °C, 12 h; (iii) phenylacetylene, CuI, PdCl2(PPh3)4, DMF/Et3N (1:1), rt, 12 h.

Scheme 5. Diversity Enhancing Functional Group Manipulations on Quinoline 16aa

Reaction conditions: (i) MeI, NaOH, DMF, rt, 5 h; (ii) NBS, AcOH, 80 °C, 5 h; (iii) phenylboronic acid, Na2CO3, Pd(PPh3)4, PhCH3/water (2:1), 85 °C, 12 h; (iv) p-tolylboronic acid, Na2CO3, Pd(PPh3)4, PhCH3/water (2:1), 105 °C, 18 h; (v) P(OEt)3/1,2-dichlorobenzene (1:1), 180 °C, 24 h. a

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experimental) and nitromethane in the presence of a base, siteselective benzannulation could be implemented and a range of isoquinolines could be accessed. Several bases like NaOMe, K2CO3, and Cs2CO3 were explored for effecting this benzannulation but under optimized reaction conditions [K2CO3 (3.0 equiv), DMSO, 110 °C, 8 h; see Table S2]; the reaction between 3-chloropyridyl ynone 15a and nitromethane afforded the 8-nitro-7-phenylisoquinolin-5ol product 17a in 75% yield (Scheme 8). The structure of 17a was secured by a single-crystal X-ray structure determination (Scheme 8), and the generality of this one-pot isoquinoline synthesis was demonstrated with seven diverse 3-chloropyridyl ynones, 15b−g, to furnish functionalized isoquinolines 17b−g, respectively, in consistent good yields (Scheme 8). The mechanism of this nitromethane-mediated benzannulation process, leading to isoquinolines, should be analogous to the one depicted for quinolines in Scheme 7. In summary, a new, simple-to-execute (one pot, table-top chemicals) synthesis of quinolines and isoquinolines by harnessing the proclivity of nitromethane as a recursive carbanion source to stitch suitably crafted o-halopyridinyl ynones via a tandem Michael addition−SNAr process has been devised. The generality of this approach, which leverages the ready availability of the pyridine bank, has been demonstrated through benzannulation of over 25 diverse pyridyl ynones to furnish the corresponding quinolines or isoquinolines and this finding augurs well for accessing polycyclic heteroaromatics and complex natural products based on these motifs.

EXPERIMENTAL SECTION

General Experimental Details. Unless otherwise noted, all reagents were used as received from commercial sources. All air- and moisture-sensitive reactions were conducted under a nitrogen or argon atmosphere in flame-dried or oven-dried glassware with magnetic stirring. Tetrahydrofuran (THF) was dried over Na and benzophenone and distilled prior to use. Reactions were monitored by thin-layer chromatography (carried out on silica plates, silica gel 60 F254, Merck) using UV light, iodine, and p-anisaldehyde for visualization. Column chromatography was carried out using silica gel (60−120 mesh or 100−200 mesh) packed in glass columns. Technical grade ethyl acetate and petroleum ether used for column chromatography were distilled prior to use. 1H NMR and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 solvents on a 400 or 500 MHz spectrometer at an ambient temperature. The coupling constant (J) is given in hertz (Hz). The chemical shifts (δ) are reported in ppm on a scale downfield from TMS and using the residual solvent peak in CDCl3 (H δ = 7.26 and C δ = 77.16 ppm) or DMSO-d6 (H δ = 2.50 and C δ = 39.52 ppm) or TMS (δ = 0.0) as an internal standard, and signal patterns are indicated as follows: s = singlet, d = doublet, dd = doublet of doublet, dt = doublet of triplet, t = triplet, q = quartet, m = multiplet, bs = broad singlet. IR spectra were recorded on an FTIR spectrophotometer. High-resolution mass spectra (HRMS) were recorded using ESI-TOF techniques. Melting points were measured with a Buchi B-540 melting apparatus. Singlecrystal X-ray data was collected on a Bruker D8 Quest CCD diffractometer using Mo Kα radiation at 298 K. Data reduction was carried out with CrysAlisproversion 171.33.55 software. Structure solution and refinements were performed with the help of the SHELX2014/7program available in the WinGX package. Preparation of Ynone Precursors. Among the ynones synthesized, 14a and 15a are known12a,c and 14b−r and 15b−g are 8734

DOI: 10.1021/acs.joc.9b00950 J. Org. Chem. 2019, 84, 8731−8742

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The Journal of Organic Chemistry Scheme 6. Scope of Polysubstituted Quinoline Synthesisa

Reaction conditions: (i) CH3NO2, NaOMe, MeOH, 80 °C, 6−12 h.

a

and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the crude material was purified by flash chromatography (35% EtOAc/hexanes) to afford ynone (14a) as a yellow solid (193 mg, 80%): mp 70−72 °C; 1H NMR (500 MHz, CDCl3) δ 8.56 (dd, J = 4.8, 2.0 Hz, 1H), 8.33 (dd, J = 7.7, 2.0 Hz, 1H), 7.66−7.64 (m, 2H), 7.52−7.48 (m, 1H), 7.43−7.40 (m, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.6, 152.5, 149.6, 140.8, 133.4, 132.8, 131.5, 128.9, 122.5, 119.7, 95.8, 88.1; IR (neat) vmax 2194, 1633 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H9ClNO 242.0367, found 242.0369. Compounds 14b−r were synthesized following the procedure for compound 14a, and their characterization is detailed below. 1-(2-Chloropyridin-3-yl)-3-(p-tolyl)prop-2-yn-1-one (14b): yellow solid (172 mg, 67%); mp 94−96 °C; 1H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.7, 1.9 Hz, 1H), 8.33 (dd, J = 7.7, 1.9 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.41 (dd, J = 7.7, 4.7 Hz, 1H), 7.22 (d, J = 7.9 Hz, 2H), 2.39 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.6, 152.3, 149.5, 142.4, 140.8, 133.4, 132.9, 129.7, 122.6, 116.5, 96.7, 88.1, 21.9; IR (neat) vmax 2191, 1629 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H11ClNO 256.0524, found 256.0526. 1-(2-Chloropyridin-3-yl)-3-(4-propylphenyl)prop-2-yn-1-one (14c): thick yellow liquid (195 mg, 69%); 1H NMR (500 MHz, CDCl3) δ 8.53 (dd, J = 4.8, 2.0 Hz, 1H), 8.32 (dd, J = 7.7, 2.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.39 (dd, J = 7.7, 4.8 Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H), 1.66−1.58 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.5, 152.3, 149.5, 147.0, 140.7, 133.4, 132.8, 129.0, 122.5, 116.7, 96.6, 88.0, 38.2, 24.2, 13.7; IR (neat) vmax 2958, 2187, 1648 cm−1; HRMS (ESI) m/z [M + Na]+ calcd for C17H14ClNNaO 306.0656, found 306. 0667. 1-(2-Chloropyridin-3-yl)-3-(4-methoxyphenyl)prop-2-yn-1-one (14d): yellow solid (180 mg, 66%); mp 94−96 °C; 1H NMR (500

Scheme 7. Possible Reaction Mechanism for Quinoline Formation

new and have been characterized. 2-Chloronicotinoyl chloride and ynones 14a−r were synthesized following a slightly modified procedure by Langer et al.12c Ynones 15a−g were synthesized following a tactically modified procedure by Muller et al.12b Synthesis of 1-(2-Chloropyridin-3-yl)-3-phenylprop-2-yn-1-one (14a). To a solution of 2-chloronicotinoyl chloride (1 mmol, 175 mg) in THF (10 mL) were added Pd(PPh3)2Cl2 (0.03 mmol, 21 mg), CuI (0.06 mmol, 11.4 mg), and Et3N (1.5 mmol, 210 μL). The reaction mixture was degassed with dry N2 for 5 min, and then 1-alkyne (phenylaceylene) (1.0 mmol, 110 μL) was added. The resulting reaction mixture was stirred for 3 h under a nitrogen atmosphere. After completion of the reaction, the mixture was diluted with water 8735

DOI: 10.1021/acs.joc.9b00950 J. Org. Chem. 2019, 84, 8731−8742

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The Journal of Organic Chemistry Scheme 8. Scope of Isoquinoline Synthesis from Variously Substituted 3-Chloropyridyl Ynonesa

Reaction conditions: (i) CH3NO2, K2CO3, DMSO, 110 °C, 8 h.

a

MHz, CDCl3) δ 8.54 (dd, J = 4.8, 2.0 Hz, 1H), 8.31 (dd, J = 7.7, 2.0 Hz, 1H), 7.61 (d, J = 8.9 Hz, 2H), 7.40 (dd, J = 7.7, 4.8 Hz, 1H), 6.92 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.6, 162.4, 152.3, 149.5, 140.7, 135.6, 133.1, 122.5, 114.7, 111.4, 97.4, 88.4, 55.6; IR (neat) vmax 2187, 1599 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H11ClNO2 272.0473, found 272.0475. 1-(2-Chloropyridin-3-yl)-3-(4-(pentyloxy)phenyl)prop-2-yn-1-one (14e): thick yellow liquid (210 mg, 64%); 1H NMR (500 MHz, CDCl3) δ 8.53 (dd, J = 4.8, 1.9 Hz, 1H), 8.30 (dd, J = 7.7, 2.0 Hz, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.39 (dd, J = 7.7, 4.8 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 3.97 (t, J = 6.5 Hz, 2H), 1.80−1.75 (m, 2H), 1.45− 1.32 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.5, 162.0, 152.2, 149.5, 140.6, 135.5, 133.1, 122.5, 115.1, 111.1, 97.6, 88.4, 68.4, 28.8, 28.2, 22.5, 14.0; IR (neat) vmax 2930, 2183, 1647 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C19H19ClNO2 328.1099, found 328.1097. 1-(2-Chloropyridin-3-yl)-3-(3-methoxyphenyl)prop-2-yn-1-one (14f): thick yellow liquid (175 mg, 64%); 1H NMR (500 MHz, CDCl3) δ 8.53 (dd, J = 4.8, 2.0 Hz, 1H), 8.32 (dd, J = 7.7, 2.0 Hz, 1H), 7.40 (dd, J = 7.7, 4.8 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.23− 7.21 (m, 1H), 7.12−7.11 (m, 1H), 7.03−7.01 (m, 1H), 3.80 (s, 3H); 13 C{1H} NMR (126 MHz, CDCl3) δ 175.5, 159.6, 152.4, 149.5, 140.8, 132.7, 130.0, 125.8, 122.5, 120.6, 118.2, 117.8, 95.6, 87.7, 55.5; IR (neat) vmax 2190, 1647 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H11ClNO2 272.0473, found 272.0474. 1-(2-Chloropyridin-3-yl)-3-(2-methoxyphenyl)prop-2-yn-1-one (14g): yellow solid (170 mg, 63%); mp 72−74 °C; 1H NMR (500 MHz, CDCl3) δ 8.51−8.49 (m, 2H), 7.53 (dd, J = 7.6, 1.6 Hz, 1H), 7.44−7.38 (m, 2H), 6.95−6.89 (m, 2H), 3.88 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.3, 162.0, 152.2, 149.5, 141.5, 135.1, 133.3, 132.3, 122.4, 120.8, 111.0, 108.8, 93.0, 92.0, 55.9; IR (neat) vmax 2190, 1633 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H11ClNO2 272.0473, found 272.0477. 1-(2-Chloropyridin-3-yl)-3-(3,5-dimethoxyphenyl)prop-2-yn-1one (14h): yellow solid (189 mg, 63%); mp 103−105 °C; 1H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.7, 1.9 Hz, 1H), 8.32 (dd, J = 7.7, 1.9 Hz, 1H), 7.41 (dd, J = 7.7, 4.8 Hz, 1H), 6.77 (d, J = 2.2 Hz, 2H), 6.58 (t, J = 2.2 Hz, 1H), 3.79 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.5, 160.9, 152.5, 149.6, 140.8, 132.7, 122.5, 120.9, 110.9, 104.9, 95.7, 87.3, 55.7; IR (neat) vmax 2198, 1648 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H13ClNO3 302.0578, found 302.0578. 1-(2-Chloropyridin-3-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-yn-1one (14i): yellow solid (195 mg, 59%); mp 120−122 °C; 1H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.7, 1.9 Hz, 1H), 8.29 (dd, J = 7.7, 1.9 Hz, 1H), 7.41 (dd, J = 7.7, 4.8 Hz, 1H), 6.87 (s, 2H), 3.89 (s,

3H), 3.86 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.5, 153.4, 152.4, 149.5, 141.9, 140.6, 133.0, 122.5, 114.2, 110.9, 96.5, 87.7, 61.1, 56.4; IR (neat) vmax 2182, 1643 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C17H15ClNO4 332.0684, found 332.0685. 1-(2-Chloropyridin-3-yl)-3-(4-fluorophenyl)prop-2-yn-1-one (14j): yellow solid (165 mg, 64%); mp 132−134 °C; 1H NMR (500 MHz, CDCl3) δ 8.57 (dd, J = 4.8, 1.3 Hz, 1H), 8.31 (dd, J = 7.6, 1.3 Hz, 1H), 7.66 (dd, J = 8.4, 5.5 Hz, 2H), 7.41 (dd, J = 7.6, 4.8 Hz, 1H), 7.14−7.10 (m, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.5, 164.5 (d, J = 254.9 Hz), 152.5, 149.7, 140.7, 135.8 (d, J = 9.0 Hz), 132.8, 122.6, 116.6 (d, J = 22.5 Hz), 115.9 (d, J = 3.4 Hz), 94.8, 88.1; IR (neat) vmax 2218, 1550 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H8ClFNO 260.0273, found 260.0273. 3-(4-Chlorophenyl)-1-(2-chloropyridin-3-yl)prop-2-yn-1-one (14k): yellow solid (175 mg, 64%); mp 152−154 °C; 1H NMR (400 MHz, CDCl3) δ 8.57 (dd, J = 4.7, 1.9 Hz, 1H), 8.31 (dd, J = 7.7, 1.9 Hz, 1H), 7.59−7.57 (m, 2H), 7.44−7.39 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.5, 152.6, 149.6, 140.8, 138.0, 134.5, 132.6, 129.4, 122.6, 118.1, 94.4, 88.7; IR (neat) vmax 2196, 1630 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H8Cl2NO 275.9977, found 275.9977. 4-(3-(2-Chloropyridin-3-yl)-3-oxoprop-1-yn-1-yl)benzonitrile (14l): yellow solid (190 mg, 71%); mp 178−179 °C; 1H NMR (500 MHz, CDCl3) δ 8.59 (dd, J = 4.7, 1.9 Hz, 1H), 8.31 (dd, J = 7.7, 2.0 Hz, 1H), 7.75−7.71 (m, 4H), 7.44 (dd, J = 7.7, 4.8 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.2, 152.9, 149.7, 140.9, 133.5, 132.5, 132.3, 124.5, 122.7, 117.9, 114.7, 92.1, 90.2; IR (neat) υmax 2232, 2201, 1654 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H8ClN2O 267.0320, found 267.0321. Methyl 4-(3-(2-Chloropyridin-3-yl)-3-oxoprop-1-yn-1-yl)benzoate (14m): yellow solid (210 mg, 70%); mp 134−136 °C; 1 H NMR (500 MHz, CDCl3) δ 8.56 (dd, J = 4.7, 1.9 Hz, 1H), 8.33 (dd, J = 7.7, 1.9 Hz, 1H), 8.07 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.42 (dd, J = 7.7, 4.8 Hz, 1H), 3.93 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.3, 166.0, 152.7, 149.7, 140.8, 133.1, 132.5, 132.4, 129.9, 124.1, 122.6, 93.8, 89.4, 52.6; IR (neat) vmax 2199, 1724, 1632 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H11ClNO3 300.0422, found 300.0422. 1-(2-Chloropyridin-3-yl)-3-(naphthalen-2-yl)prop-2-yn-1-one (14n): yellow solid (180 mg, 62%); mp 77−79 °C; 1H NMR (500 MHz, CDCl3) δ 8.58 (dd, J = 4.7, 1.9 Hz, 1H), 8.38 (dd, J = 7.7, 1.9 Hz, 1H), 8.23 (s, 1H), 7.88−7.86 (m, 3H), 7.63 (d, J = 8.5 Hz, 1H), 7.61−7.54 (m, 2H), 7.43 (dd, J = 7.7, 4.8 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.6, 152.5, 149.7, 140.9, 135.0, 134.3, 132.9, 132.7, 128.8, 128.51, 128.47, 128.4, 128.1, 127.3, 122.6, 116.9, 96.5, 8736

DOI: 10.1021/acs.joc.9b00950 J. Org. Chem. 2019, 84, 8731−8742

Note

The Journal of Organic Chemistry 88.4; IR (neat) vmax 2194, 1639 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C18H11ClNO 292.0524, found 292.0526. 1-(2-Chloropyridin-3-yl)hept-2-yn-1-one (14o): yellow liquid (160 mg, 72%); 1H NMR (400 MHz, CDCl3) δ 8.48 (dd, J = 4.7, 1.9 Hz, 1H), 8.24 (dd, J = 7.7, 1.9 Hz, 1H), 7.35 (dd, J = 7.7, 4.8 Hz, 1H), 2.45 (t, J = 7.1 Hz, 2H), 1.63−1.55 (m, 2H), 1.47−1.38 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.7, 152.1, 149.3, 140.9, 132.6, 122.4, 99.8, 80.7, 29.5, 22.1, 19.1, 13.5; IR (neat) vmax 2937, 2218, 1656 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C12H13ClNO 222.0680, found 222.0680. 1-(2-Chloropyridin-3-yl)oct-2-yn-1-one (14p): yellow liquid (180 mg, 77%); 1H NMR (500 MHz, CDCl3) δ 8.48 (dd, J = 4.7, 1.9 Hz, 1H), 8.24 (dd, J = 7.7, 1.8 Hz, 1H), 7.35 (dd, J = 7.7, 4.8 Hz, 1H), 2.44 (t, J = 7.1 Hz, 2H), 1.64−1.58 (m, 2H), 1.42−1.27 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.7, 152.1, 149.4, 140.8, 132.7, 122.3, 99.8, 80.8, 31.1, 27.2, 22.1, 19.4, 13.9; IR (neat) vmax 2930, 2218, 1656 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C13H15ClNO 236.0837, found 236.0838. 1-(2-Chloropyridin-3-yl)undec-2-yn-1-one (14q): yellow liquid (200 mg, 72%); 1H NMR (500 MHz, CDCl3) δ 8.49 (dd, J = 4.8, 1.8 Hz, 1H), 8.24 (dd, J = 7.7, 1.8 Hz, 1H), 7.35 (dd, J = 7.7, 4.8 Hz, 1H), 2.44 (t, J = 7.1 Hz, 2H), 1.64−1.58 (m, 2H), 1.45−1.37 (m, 2H), 1.30−1.23 (m, 8H), 0.83 (t, J = 6.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.7, 152.1, 149.4, 140.9, 132.6, 122.3, 99.9, 80.7, 31.8, 29.1, 29.0 (2C), 27.5, 22.7, 19.4, 14.1; IR (neat) vmax 2924, 2218, 1658 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H21ClNO 278.1306, found 278.1305. The synthesis of 2-Chloro-6-methylnicotinoyl chlorides was similar to that of 2-chloronicotinoyl chloride (vide supra). 1-(2-Chloro-6-methylpyridin-3-yl)-3-phenylprop-2-yn-1-one (14r): yellow solid (166 mg, 65%); mp 70−72 °C ; 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J = 7.8 Hz, 1H), 7.65−7.63 (m, 2H), 7.51− 7.47 (m, 1H), 7.43−7.39 (m, 2H), 7.24 (d, J = 7.9 Hz, 1H), 2.62 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.4, 163.3, 149.0, 141.3, 133.3, 131.3, 129.8, 128.9, 122.1, 119.9, 95.2, 88.2, 24.6; IR (neat) vmax 2194, 1638, 1580, 1375 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H11ClNO 256.0524, found 256.0525. Synthesis of 8-Nitro-7-phenylquinolin-5-ol (16a). In an ovendried sealed tube were added ynone 14a (0.2 mmol, 48.2 mg) and nitromethane (0.6 mmol, 32 μL), and to this were added MeOH (2 mL) and 30% NaOMe in MeOH (0.6 mmol, 111 μL); the reaction mixture was stirred at 80 °C for 6 h. After the consumption of the starting material (monitored by TLC), the reaction was quenched with a saturated solution of aq NH4Cl (10 mL), extracted with EtOAc (3 × 20 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (60% EtOAC/hexane) to obtain 16a as a pale yellow solid (42.5 mg, 80%): mp 241−243 °C; 1H NMR (500 MHz, DMSO) δ 11.71 (bs, 1H), 8.99 (dd, J = 4.2, 1.7 Hz, 1H), 8.64 (dd, J = 8.5, 1.7 Hz, 1H), 7.66 (dd, J = 8.5, 4.2 Hz, 1H), 7.54−7.46 (m, 5H), 6.93 (s, 1H); 13C{1H} NMR (126 MHz, DMSO) δ 154.9, 152.9, 140.2, 139.4, 136.0, 134.6, 131.3, 129.1, 129.0, 127.9, 122.0, 118.6, 108.9; IR (neat) vmax 2919, 1519, 1361 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H11N2O3 267.0764, found 267.0768. Gram-Scale Synthesis of 16a. By following the general procedure, using ynone 14a (5 mmol), nitromethane (15 mmol), and 30% NaOMe in MeOH (15 mmol), compound 16a was prepared (1.02 g, 77%). Compounds 16b−r were synthesized following the procedure for compound 16a. The reaction time for 16b−f, 16h−n, and 16r was 6 h and for 16g and 16o−q was 12 h. Characterization of all compounds is detailed below. 8-Nitro-7-(p-tolyl)quinolin-5-ol (16b): yellow solid (40.5 mg, 72%); mp 225−227 °C; 1H NMR (400 MHz, DMSO) δ 11.59 (bs, 1H), 8.98 (dd, J = 4.2, 1.6 Hz, 1H), 8.62 (dd, J = 8.5, 1.6 Hz, 1H), 7.65 (dd, J = 8.5, 4.2 Hz, 1H), 7.37−7.31 (m, J = 8.2 Hz, 4H), 6.92 (s, 1H), 2.36 (s, 3H); 13C{1H} NMR (101 MHz, DMSO) δ 154.8, 152.8, 140.2, 139.4, 138.6, 134.5, 133.1, 131.2, 129.6, 127.7, 121.8, 118.5, 108.8, 20.7; IR (neat) vmax 2918, 1523, 1356 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H13N2O3 281.0921, found 281.0927.

8-Nitro-7-(4-propylphenyl)quinolin-5-ol (16c): yellow solid (43.5 mg, 71%); mp 223−225 °C; 1H NMR (500 MHz, DMSO) δ 11.62 (bs, 1H), 8.98 (dd, J = 4.1, 1.5 Hz, 1H), 8.62 (dd, J = 8.5, 1.5 Hz, 1H), 7.64 (dd, J = 8.5, 4.2 Hz, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 6.93 (s, 1H), 2.61 (t, J = 7.5 Hz, 2H), 1.65−1.58 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (126 MHz, DMSO) δ 154.8, 152.8, 143.2, 140.2, 139.4, 134.5, 133.3, 131.2, 129.0, 127.7, 121.8, 118.5, 108.9, 36.9, 23.8, 13.7; IR (neat) vmax 2922, 1515, 1355 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C18H17N2O3 309.1234, found 309.1238. 7-(4-Methoxyphenyl)-8-nitroquinolin-5-ol (16d): yellow solid (42.6 mg, 72%); mp 192−194 °C; 1H NMR (500 MHz, DMSO) δ 11.67 (bs, 1H), 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.60 (dd, J = 8.5, 1.7 Hz, 1H), 7.62 (dd, J = 8.5, 4.2 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.92 (s, 1H), 3.80 (s, 3H); 13C{1H} NMR (126 MHz, DMSO) δ 159.8, 154.7, 152.7, 140.3, 139.4, 134.3, 131.2, 129.2, 128.1, 121.7, 118.4, 114.5, 108.9, 55.3; IR (neat) vmax 2918, 1509, 1354 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H13N2O4 297.0870, found 297.0878. 8-Nitro-7-(4-(pentyloxy)phenyl)quinolin-5-ol (16e): yellow solid (50 mg, 71%); mp 166−168 °C; 1H NMR (500 MHz, DMSO) δ 11.54 (bs, 1H), 8.97 (dd, J = 4.2, 1.7 Hz, 1H), 8.61 (dd, J = 8.5, 1.7 Hz, 1H), 7.63 (dd, J = 8.5, 4.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.91 (s, 1H), 4.01 (t, J = 6.5 Hz, 2H), 1.76−1.70 (m, 2H), 1.43−1.31 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (126 MHz, DMSO) δ 159.3, 154.6, 152.7, 140.3, 139.3, 134.2, 131.1, 129.1, 127.8, 121.7, 118.4, 114.9, 108.9, 67.6, 28.3, 27.7, 21.8, 13.8; IR (neat) vmax 3175, 2933, 1522, 1318 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C20H21N2O4 353.1496, found 353.1498. 7-(3-Methoxyphenyl)-8-nitroquinolin-5-ol (16f): yellow solid (42 mg, 71%); mp 216−218 °C; 1H NMR (500 MHz, DMSO) δ 11.59 (bs, 1H), 8.99 (dd, J = 4.2, 1.7 Hz, 1H), 8.63 (dd, J = 8.5, 1.7 Hz, 1H), 7.66 (dd, J = 8.5, 4.2 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.07 (dd, J = 8.0, 2.2 Hz, 1H), 7.03−7.00 (m, 2H), 6.94 (s, 1H), 3.80 (s, 3H); 13 C{1H} NMR (126 MHz, DMSO) δ 159.4, 154.8, 152.9, 140.1, 139.4, 137.3, 134.4, 131.2, 130.2, 121.9, 120.1, 118.7, 114.4, 113.6, 108.8, 55.2; IR (neat) vmax 3080, 2996, 1513, 1360 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H13N2O4 297.0870, found 297.0869. 7-(2-Methoxyphenyl)-8-nitroquinolin-5-ol (16g): yellow solid (41 mg, 69%); mp 222−224 °C; 1H NMR (500 MHz, DMSO) δ 11.47 (bs, 1H), 8.97 (dd, J = 4.2, 1.7 Hz, 1H), 8.62 (dd, J = 8.5, 1.7 Hz, 1H), 7.65 (dd, J = 8.5, 4.2 Hz, 1H), 7.47−7.43 (m, 1H), 7.24 (dd, J = 7.5, 1.7 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 7.06−7.03 (m, 1H), 6.84 (s, 1H), 3.71 (s, 3H); 13C{1H} NMR (126 MHz, DMSO) δ 156.1, 154.3, 152.6, 140.2, 139.9, 132.8, 131.1, 130.6, 129.8, 124.6, 121.8, 120.6, 118.7, 111.7, 109.9, 55.5; IR (neat) vmax 2923, 1517, 1353 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H13N2O4 297.0870, found 297.0852. 7-(3,5-Dimethoxyphenyl)-8-nitroquinolin-5-ol (16h): yellow solid (45 mg, 69%); mp 230−232 °C; 1H NMR (500 MHz, DMSO) δ 11.62 (bs, 1H), 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.63 (dd, J = 8.5, 1.7 Hz, 1H), 7.65 (dd, J = 8.5, 4.2 Hz, 1H), 6.94 (s, 1H), 6.62 (t, J = 2.2 Hz, 1H), 6.59 (d, J = 2.2 Hz, 2H), 3.78 (s, 6H); 13C{1H} NMR (126 MHz, DMSO) δ 160.7, 154.8, 152.8, 140.1, 139.4, 137.8, 134.4, 131.2, 121.9, 118.7, 108.7, 106.2, 100.5, 55.4; IR (neat) vmax 3078, 3002, 1517, 1342 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C17H15N2O5 327.0975, found 327.0975. 8-Nitro-7-(3,4,5-trimethoxyphenyl)quinolin-5-ol (16i): yellow solid (46 mg, 65%); mp 220−222 °C; 1H NMR (400 MHz, DMSO) δ 11.65 (bs, 1H), 8.99 (dd, J = 4.2, 1.6 Hz, 1H), 8.63 (dd, J = 8.5, 1.6 Hz, 1H), 7.65 (dd, J = 8.5, 4.2 Hz, 1H), 6.98 (s, 1H), 6.77 (s, 2H), 3.80 (s, 6H), 3.73 (s, 3H); 13C{1H} NMR (126 MHz, DMSO) δ 154.7, 153.1, 152.8, 140.1, 139.5, 138.0, 134.5, 131.3, 131.2, 121.9, 118.6, 108.9, 105.5, 60.1, 56.0; IR (neat) vmax 3260, 2938, 1519, 1348 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C18H17N2O6 357.1081, found 357.1081. 7-(4-Fluorophenyl)-8-nitroquinolin-5-ol (16j): yellow solid (42 mg, 74%); mp 185−187 °C; 1H NMR (400 MHz, DMSO) δ 11.72 (bs, 1H), 8.99 (dd, J = 4.2, 1.7 Hz, 1H), 8.63 (dd, J = 8.5, 1.7 Hz, 8737

DOI: 10.1021/acs.joc.9b00950 J. Org. Chem. 2019, 84, 8731−8742

Note

The Journal of Organic Chemistry

(s, 1H), 8.50 (d, J = 8.6 Hz, 1H), 7.54−7.48 (m, 4H), 7.46−7.43 (m, 2H), 6.85 (s, 1H), 2.64 (s, 3H); 13C{1H} NMR (101 MHz, DMSO) δ 161.8, 154.7, 139.8, 139.2, 136.2, 134.4, 131.2, 129.0, 128.9, 127.8, 122.6, 116.8, 108.2, 25.1; IR (neat) vmax 3454, 2921, 1512, 1362 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H13N2O3 281.0921, found 281.0922. Synthesis of (Z)-1-(2-Chloropyridin-3-yl)-3-nitro-3-phenylprop-2en-1-one (18). To an oven-dried sealed tube were added ynone 14a (0.2 mmol, 48.2 mg) and nitromethane (0.6 mmol, 32 μL), and to this, MeOH (2 mL) and 30% NaOMe in MeOH (0.6 mmol, 109 μL) were added. The reaction mixture was stirred for 6 h at rt. After complete consumption of the starting material (TLC), the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated, and the crude material was purified by silica gel column chromatography (45% EtOAC/ Hexane) to obtain 18 as a pale yellow solid (45 mg, 75%): mp 110− 112 °C; 1H NMR (500 MHz, CDCl3) δ 8.55 (dd, J = 4.8, 1.9 Hz, 1H), 7.97 (dd, J = 7.6, 1.9 Hz, 1H), 7.58−7.56 (m, 2H), 7.49−7.45 (m, 3H), 7.40 (dd, J = 7.6, 4.8 Hz, 1H), 7.34 (s, 1H), 6.01 (s, 2H); 13 C{1H} NMR (126 MHz, CDCl3) δ 190.7, 152.1, 148.0, 144.4, 139.6, 137.9, 135.7, 130.9, 129.5, 129.3, 127.0, 123.0, 74.1; IR (neat) vmax 2919, 1650, 1608, 1538, 1394 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H12ClN2O3 303.0531, found 303.0538. Compound 18 (0.1 mmol, 30.2 mg) was further reacted with 30% NaOMe (0.1 mmol, 18 μL) in MeOH (2 mL) under our standard conditions (80 °C for 6 h) to afford compound 16a (21 mg, 78%). Synthesis of 8-Nitro-7-phenylquinolin-5-yl trifluoromethanesulfonate (19). To a solution of 8-nitro-7-phenylquinolin-5-ol 16a (0.5 mmol, 133 mg) and pyridine (1 mmol, 80 μL) in dichloromethane (5 mL) was added trifluoromethanesulfonic anhydride (0.6 mmol, 101 μL) at 0 °C, and the reaction mixture was stirred (12 h at rt under N2). The reaction mixture was diluted with water and extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (20% EtOAC/hexane) to obtain 19 as a white solid (155 mg, 78%): mp 113−115 °C; 1H NMR (500 MHz, CDCl3) δ 9.14 (dd, J = 4.2, 1.6 Hz, 1H), 8.49 (dd, J = 8.6, 1.6 Hz, 1H), 7.73 (dd, J = 8.6, 4.2 Hz, 1H), 7.64 (s, 1H), 7.54−7.50 (m, 5H); 13C{1H} NMR (126 MHz, CDCl3) δ 153.9, 146.8, 144.5, 140.6, 134.2, 134.1, 130.1, 129.7, 129.5, 128.4, 124.1, 121.7, 120.6, 118.8 (q, J = 320.7 Hz); IR (neat) vmax 1541, 1407, 1344, 1047 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H10F3N2O5S 399.0257, found 399.0257. Synthesis of 8-Nitro-5,7-diphenylquinoline (20). To a solution of 8-nitro-7-phenylquinolin-5-yl trifluoromethanesulfonate 19 (0.1 mmol, 39.8 mg), phenylboronic acid (0.12 mmol, 15 mg), and K2CO3 (0.3 mmol, 41 mg) in a toluene (1 mL) and water (1 mL) mixture (1:1) was added Pd(PPh3)4 (0.01 mmol, 11.5 mg). The reaction mixture was degassed with dry N2 for 5 min and then stirred at 100 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (20% EtOAC/Hexane) to obtain 20 as a pale yellow solid (27 mg, 83%): mp 153−155 °C; 1H NMR (400 MHz, CDCl3) δ 9.04 (dd, J = 4.2, 1.6 Hz, 1H), 8.31 (dd, J = 8.6, 1.6 Hz, 1H), 7.60 (s, 1H), 7.59−7.55 (m, 3H), 7.54−7.47 (m, 8H); 13 C{1H} NMR (126 MHz, CDCl3) δ 152.4, 146.9, 142.7, 140.2, 137.8, 135.7, 134.6, 133.4, 130.0, 129.3, 129.2, 129.0, 128.9, 128.7, 128.6, 126.5, 122.7; IR (neat) vmax 3056, 1528, 1372, 1336 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C21H15N2O2 327.1128, found 327.1123. Synthesis of 8-Nitro-7-phenyl-5-(phenylethynyl)quinolone (21). To a solution of 8-nitro-7-phenylquinolin-5-yl trifluoromethanesulfonate 19 (0.1 mmol, 39.8 mg) in a 1:1 mixture of DMF (1.5 mL) and Et3N (1.5 mL) were added PdCl2(PPh3)2 (7 mg, 0.01 mmol) and CuI (3.8 mg, 0.02 mmol). The reaction mixture was degassed with dry N2 for 5 min, and phenylacetylene (22 μL, 0.2 mmol) was added. The resulting reaction mixture was stirred for 12 h, after which it was

1H), 7.65 (dd, J = 8.5, 4.2 Hz, 1H), 7.54−7.50 (m, 2H), 7.39−7.33 (m, 2H), 6.91 (s, 1H); 13C{1H} NMR (101 MHz, DMSO) δ 162.5 (d, J = 246.7 Hz), 154.9, 153.0, 140.2, 139.5, 133.7, 132.4 (d, J = 3.2 Hz), 131.3, 130.2 (d, J = 8.6 Hz), 122.0, 118.7, 116.1 (d, J = 21.8 Hz), 108.8; IR (neat) vmax 3167, 2920, 1503, 1360 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H10FN2O3 285.0670, found 285.0671. 7-(4-Chlorophenyl)-8-nitroquinolin-5-ol (16k): yellow solid (45 mg, 75%); mp 222−224 °C; 1H NMR (400 MHz, DMSO) δ 11.70 (bs, 1H), 9.00 (dd, J = 4.2, 1.6 Hz, 1H), 8.64 (dd, J = 8.5, 1.6 Hz, 1H), 7.67 (dd, J = 8.5, 4.2 Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 6.90 (s, 1H); 13C{1H} NMR (101 MHz, DMSO) δ 155.1, 153.0, 140.1, 139.4, 134.8, 134.1, 133.5, 131.3, 129.8, 129.1, 122.1, 118.8, 108.6; IR (neat) vmax 3069, 2999, 1517, 1354 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H10ClN2O3 301.0374, found 301.0373. 4-(5-Hydroxy-8-nitroquinolin-7-yl)benzonitrile (16l): yellow solid (43 mg, 74%); mp 194−196 °C; 1H NMR (500 MHz, DMSO) δ 11.80 (bs, 1H), 9.02 (dd, J = 4.2, 1.7 Hz, 1H), 8.66 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.71−7.66 (m, 3H), 6.91 (s, 1H); 13 C{1H} NMR (126 MHz, DMSO) δ 155.3, 153.2, 140.6, 140.0, 139.2, 133.1, 132.9, 131.3, 129.0, 122.3, 119.1, 118.3, 111.9, 108.3; IR (neat) vmax 3072, 2921, 2229, 1525, 1353 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H10N3O3 292.0717, found 292.0717. Methyl 4-(5-Hydroxy-8-nitroquinolin-7-yl)benzoate (16m): yellow solid (50.5 mg, 78%); mp 220−222 °C; 1H NMR (500 MHz, DMSO) δ 11.87 (s, 1H), 8.99 (dd, J = 4.2, 1.3 Hz, 1H), 8.63 (dd, J = 8.5, 1.3 Hz, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.66 (dd, J = 8.5, 4.2 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 6.93 (s, 1H), 3.87 (s, 3H); 13C{1H} NMR (126 MHz, DMSO) δ 165.7, 155.1, 153.0, 140.6, 140.1, 139.3, 133.6, 131.3, 130.1, 129.7, 128.3, 122.2, 119.0, 108.4, 52.3; IR (neat) vmax 3078, 2951, 1723, 1561, 1358 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C17H13N2O5 325.0819, found 325.0818. 7-(Naphthalen-2-yl)-8-nitroquinolin-5-ol (16n): yellow solid (40 mg, 63%); mp 246−248 °C; 1H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 9.00 (dd, J = 4.3, 1.7 Hz, 1H), 8.66 (dd, J = 8.5, 1.7 Hz, 1H), 8.06−7.98 (m, 4H), 7.67 (dd, J = 8.5, 4.3 Hz, 1H), 7.61−7.56 (m, 3H), 7.04 (s, 1H); 13C{1H} NMR (126 MHz, DMSO) δ 154.9, 152.9, 140.2, 139.7, 134.7, 133.5, 132.67, 132.66, 131.3, 128.7, 128.2, 127.6, 127.2, 127.1, 126.9, 125.4, 121.9, 118.7, 109.1; IR (neat) vmax 3205, 3053, 1514, 1354 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C19H13N2O3 317.0921, found 317.0922. 7-Butyl-8-nitroquinolin-5-ol (16o): yellow solid (38 mg, 77%); mp 188−190 °C; 1H NMR (500 MHz, DMSO) δ 11.36 (bs, 1H), 8.91 (dd, J = 4.2, 1.6 Hz, 1H), 8.54 (dd, J = 8.4, 1.6 Hz, 1H), 7.57 (dd, J = 8.4, 4.2 Hz, 1H), 6.86 (s, 1H), 2.65 (t, J = 7.6 Hz, 2H), 1.62−1.56 (m, 2H), 1.35−1.27 (m, 2H), 0.87 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (126 MHz, DMSO) δ 154.6, 152.3, 140.3, 140.2, 135.7, 131.0, 121.3, 118.0, 108.4, 32.1, 30.7, 21.8, 13.6; IR (neat) vmax 2925, 1517, 1355 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C13H15N2O3 247.1077, found 247.1078. 8-Nitro-7-pentylquinolin-5-ol (16p): yellow solid (39 mg, 75%); mp 186−188 °C; 1H NMR (400 MHz, DMSO) δ 11.34 (bs, 1H), 8.91 (dd, J = 4.2, 1.7 Hz, 1H), 8.55 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 (dd, J = 8.5, 4.3 Hz, 1H), 6.85 (s, 1H), 2.64 (t, J = 7.6 Hz, 2H), 1.65− 1.57 (m, 2H), 1.31−1.26 (m, J = 8.2, 4.8 Hz, 4H), 0.85 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO) δ 154.6, 152.4, 140.3, 140.2, 135.8, 131.1, 121.4, 118.1, 108.4, 30.9, 30.8, 29.7, 21.8, 13.8; IR (neat) vmax 2924, 1516, 1355 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H17N2O3 261.1234, found 261.1233. 8-Nitro-7-octylquinolin-5-ol (16q): yellow solid (40 mg, 66%); mp 182−184 °C; 1H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 8.91 (dd, J = 4.2, 1.7 Hz, 1H), 8.54 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 (dd, J = 8.5, 4.3 Hz, 1H), 6.85 (s, 1H), 2.64 (t, J = 7.5 Hz, 2H), 1.64−1.56 (m, 2H), 1.28−1.22 (m, 10H), 0.83 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO) δ 154.6, 152.3, 140.3, 140.2, 135.8, 131.1, 121.3, 118.0, 108.4, 31.2, 30.9, 30.0, 28.6(2C), 28.5, 22.1, 13.9; IR (neat) vmax 2921, 1518, 1353 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C17H23N2O3 303.1703, found 303.1704. 2-Methyl-8-nitro-7-phenylquinolin-5-ol (16r): yellow solid (42 mg, 75%); mp 210−212 °C; 1H NMR (400 MHz, DMSO) δ 11.48 8738

DOI: 10.1021/acs.joc.9b00950 J. Org. Chem. 2019, 84, 8731−8742

Note

The Journal of Organic Chemistry diluted with water, extracted with ethyl acetate (3 × 20 mL), dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography (25% EtOAc/hexanes) to afford 21 as a pale yellow solid (28 mg, 80%): mp 122−124 °C; 1H NMR (500 MHz, CDCl3) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1H), 8.78 (dd, J = 8.5, 1.6 Hz, 1H), 7.87 (s, 1H), 7.66−7.63 (m, 3H), 7.56−7.54 (m, 2H), 7.50− 7.47 (m, 3H), 7.44−7.43 (m, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 152.9, 147.0, 139.8, 135.2, 134.7, 133.8, 132.1, 132.0, 129.6, 129.5, 129.2, 128.8, 128.5, 128.1, 123.7, 123.2, 122.2, 97.5, 84.8; IR (neat) vmax 3057, 2210, 1559, 1536, 1373 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C23H15N2O2 351.1128, found 351.1124. Synthesis of 5-Methoxy-8-nitro-7-phenylquinoline (22). Iodomethane (2.5 mmol, 157 μL) was added to a mixture of 8-nitro-7phenylquinolin-5-ol (16a) (2 mmol, 532 mg) and NaOH (2 mmol, 80 mg) in dry DMF at 0 °C. The reaction mixture was stirred (5 h at rt), and after consumption of the starting material (TLC), it was diluted with H2O (5 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (35% EtOAC/hexane) to obtain compound 22 as a pale yellow solid (500 mg, 89%): mp 138−140 °C; 1 H NMR (500 MHz, CDCl3) δ 9.01 (dd, J = 4.3, 1.7 Hz, 1H), 8.61 (dd, J = 8.5, 1.7 Hz, 1H), 7.54−7.49 (m, 3H), 7.48−7.45 (m, 3H), 6.82 (s, 1H), 4.07 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 155.8, 152.8, 141.7, 140.8, 136.5, 135.1, 131.1, 129.2, 129.1, 128.3, 121.8, 120.0, 105.6, 56.4; IR (neat) vmax 2942, 1590, 1520, 1352 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H13N2O3 281.0921, found 281.0923. Synthesis of 3,6-Dibromo-5-methoxy-8-nitro-7-phenylquinoline (23). NBS (2.5 mmol, 445 mg) was added to a solution of 5-methoxy8-nitro-7-phenylquinoline (22) (1 mmol, 280 mg) in acetic acid (5 mL), and the reaction mixture was stirred at 80 °C for 5 h. After consumption of the starting material (TLC), acetic acid was removed under vacuo and the crude reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (20% EtOAC/Hexane) to obtain 23 as a white solid (310 mg, 71%): mp 227−229 °C; 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 7.49−7.47 (m, 3H), 7.36−7.33 (m, 2H), 4.10 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 154.1, 153.8, 145.4, 137.5, 136.5, 134.1, 132.4, 129.7, 129.2, 128.7, 124.4, 120.2, 117.0, 62.5; IR (neat) vmax 3075, 2943, 1526, 1339, 687 cm−1 ; HRMS (ESI) m/z [M + H] + calcd for C16H11Br2N2O3 436.9131, found 436.9124. Synthesis of 6-Bromo-5-methoxy-8-nitro-3,7-diphenylquinoline (24). To a solution of 3,6-dibromo-5-methoxy-8-nitro-7-phenylquinoline (23) (0.2 mmol, 88 mg), phenylboronic acid (0.25 mmol, 30.5 mg), and Na2CO3 (0.6 mmol, 64 mg) in a 2:1 mixture of toluene (4 mL) and water (2 mL) was added Pd(PPh3)4 (0.02 mmol, 23 mg). The reaction mixture was degassed with dry N2 and further stirred at 85 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (3 × 10 mL), and the combined organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (20% EtOAC/Hexane) to obtain 24 as a white solid (66 mg, 76%): mp 223−225 °C; 1H NMR (500 MHz, CDCl3) δ 9.29 (d, J = 2.2 Hz, 1H), 8.63 (d, J = 2.2 Hz, 1H), 7.75−7.73 (m, 2H), 7.60−7.57 (m, 2H), 7.54−7.48 (m, 4H), 7.39−7.38 (m, 2H), 4.13 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 154.8, 152.6, 145.4, 138.4, 136.8, 136.4, 135.7, 134.4, 129.6, 129.5, 129.4, 129.2, 128.6, 127.7, 123.5, 116.1, 62.4; IR (neat) vmax 2921, 1534, 1357, 694 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C22H16BrN2O3 435.0399, found 435.0399. Synthesis of 5-Methoxy-8-nitro-3,7-diphenyl-6-(p-tolyl)quinolone (25). To a solution of 6-bromo-5-methoxy-8-nitro-3,7diphenylquinoline (24) (0.1 mmol, 43.5 mg), p-tolylboronic acid (0.15 mmol, 20.4 mg), and Na2CO3 (0.3 mmol, 32 mg) in a 2:1 mixture of toluene (2 mL) and water (1 mL) was added Pd(PPh3)4 (0.01 mmol, 11.5 mg). The reaction mixture was degassed with dry

N2 and further stirred at 105 °C for 18 h. The reaction mixture was diluted with water, extracted with EtOAc (2 × 10 mL), washed with brine (10 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (20% EtOAC/Hexane) to obtain 25 as a white solid (36 mg, 80%): mp 254−256 °C; 1H NMR (500 MHz, CDCl3) δ 9.28 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.3 Hz, 1H), 7.78−7.71 (m, 2H), 7.59−7.56 (m, 2H), 7.51−7.48 (m, 1H), 7.24−7.20 (m, 3H), 7.15−7.13 (m, 2H), 7.05−7.01 (m, 4H), 3.53 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 154.5, 152.2, 145.3, 138.7, 137.4, 137.3, 135.7, 135.4, 134.0, 131.8, 131.6, 130.7, 129.7, 129.5, 128.9, 128.8, 128.4, 128.3, 128.1, 127.7, 123.1, 61.9, 21.4; IR (neat) vmax 3041, 2916, 1526, 1340 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C29H23N2O3 447.1703, found 447.1704. Synthesis of 5-Methoxy-11H-pyrido[2,3-a]carbazole (26). To an oven-dried sealed tube were added compound 22 (0.1 mmol, 28 mg), 1,2-dichlorobenzene (1 mL), and triethylphosphite (1 mL), and the reaction mixture was stirred at 180 °C for 24 h. The crude material was purified by silica gel column chromatography (35% EtOAC/ Hexane) to obtain 26 as a pale yellow solid (20 mg, 80%): mp 182− 184 °C; 1H NMR (400 MHz, CDCl3) δ 10.80 (s, 1H), 8.96 (dd, J = 4.4, 1.7 Hz, 1H), 8.75 (dd, J = 8.4, 1.7 Hz, 1H), 8.13−8.11 (m, 1H), 7.53 (s, 1H), 7.52−7.46 (m, 2H), 7.44−7.41 (m, 1H), 7.30−7.27 (m, 1H), 4.13 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 149.1, 148.9, 139.4, 137.7, 132.2, 130.4, 125.4, 124.0, 120.6, 120.2, 120.1, 119.9, 119.4, 111.8, 97.9, 56.2 ; IR (neat) vmax 3208, 3162, 2930, 1622, 1374 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H13N2O 249.1022, found 249.1022. Synthesis of 1-(3-Chloropyridin-4-yl)-3-phenylprop-2-yn-1-one (15a). Oxalyl chloride (1.00 mmol, 86 μL) was added dropwise to a solution of 3-chloroisonicotinic acid (1 mmol, 157 mg) in dry THF (10 mL) under N2 at rt (water bath). The mixture was further stirred for 1 h and then at 50 °C for 4 h and cooled to rt. PdCl2(PPh3)2 (0.03 mmol, 21 mg), CuI (0.06 mmol, 11.4 mg), and dry triethylamine (3.00 mmol, 420 μL) were successively added. The reaction mixture was degassed with dry N2, and 1-alkyne (phenylacetylene) (1.0 mmol, 110 μL) was added; the mixture was further stirred for 3 h. After completion, the reaction was diluted with water, extracted with ethyl acetate (3 × 20 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography (35% EtOAc/hexanes) to afford 15a as a yellow solid (170 mg, 70%): mp 80−82 °C; 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.68 (d, J = 4.9 Hz, 1H), 7.80 (d, J = 4.9 Hz, 1H), 7.66− 7.64 (m, 2H), 7.54−7.49 (m, 1H), 7.44−7.40 (m, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.4, 151.8, 148.5, 142.0, 133.5, 131.7, 129.3, 128.9, 124.1, 119.5, 96.4, 88.0; IR (neat) vmax 2195, 1639 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H9ClNO 242.0367, found 242.0368. Compounds 15b−g were synthesized in a manner similar to that for 15a. 1-(3-Chloropyridin-4-yl)-3-(p-tolyl)prop-2-yn-1-one (15b): yellow solid (155 mg, 61%); mp 96−98 °C; 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 7.80 (d, J = 5.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 2.41 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.3, 151.6, 148.4, 142.6, 141.9, 133.4, 129.6, 129.2, 124.0, 116.2, 97.1, 87.9, 21.9; IR (neat) vmax 2190, 1633 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H11ClNO 256.0524, found 256.0525. 1-(3-Chloropyridin-4-yl)-3-(4-methoxyphenyl)prop-2-yn-1-one (15c): yellow solid (160 mg, 59%); mp 106−108 °C; 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 8.66 (d, J = 4.7 Hz, 1H), 7.78 (d, J = 4.9 Hz, 1H), 7.60 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.4, 162.5, 151.7, 148.4, 142.4, 135.7, 129.3, 124.1, 114.7, 111.2, 98.1, 88.4, 55.6; IR (neat) vmax 2185, 1630 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H11ClNO2 272.0473, found 272.0471. 1-(3-Chloropyridin-4-yl)-3-(4-fluorophenyl)prop-2-yn-1-one (15d): yellow solid (158 mg, 61%); mp 105−107 °C; 1H NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 8.68 (d, J = 4.9 Hz, 1H), 7.78 (d, J = 4.9 Hz, 1H), 7.68−7.65 (m, 2H), 7.15−7.11 (m, 2H); 13C{1H} NMR 8739

DOI: 10.1021/acs.joc.9b00950 J. Org. Chem. 2019, 84, 8731−8742

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The Journal of Organic Chemistry (126 MHz, CDCl3) δ 175.3, 164.6 (d, J = 255.4 Hz), 151.8, 148.5, 142.0, 135.9 (d, J = 9.1 Hz), 129.3, 124.0, 116.6 (d, J = 22.4 Hz), 115.7 (d, J = 3.4 Hz), 95.3, 88.0; IR (neat) vmax 2199, 1636 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H8ClFNO 260.0273, found 260.0275. 1-(3-Chloropyridin-4-yl)hept-2-yn-1-one (15e): yellow liquid (155 mg, 70%); 1H NMR (500 MHz, CDCl3) δ 8.70 (s, 1H), 8.63 (d, J = 4.9 Hz, 1H), 7.71 (d, J = 4.9 Hz, 1H), 2.48 (t, J = 7.1 Hz, 2H), 1.66− 1.60 (m, 2H), 1.50−1.43 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.7, 151.7, 148.4, 142.1, 129.2, 124.2, 100.6, 80.8, 29.6, 22.2, 19.2, 13.6; IR (neat) vmax 2934, 2202, 1660 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C12H13ClNO 222.0680, found 222.0669. 1-(3-Chloropyridin-4-yl)oct-2-yn-1-one (15f): yellow liquid (170 mg, 72%); 1H NMR (500 MHz, CDCl3) δ 8.70 (s, 1H), 8.62 (d, J = 4.9 Hz, 1H), 7.71 (d, J = 4.9 Hz, 1H), 2.47 (t, J = 7.2 Hz, 2H), 1.67− 1.61 (m, 2H), 1.44−1.30 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.7, 151.6, 148.3, 142.0, 129.2, 124.2, 100.7, 80.7, 31.2, 27.2, 22.2, 19.4, 14.0; IR (neat) vmax 2928, 2203, 1659 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C13H15ClNO 236.0837, found 236.0837. 1-(3-Chloropyridin-4-yl)undec-2-yn-1-one (15g): yellow liquid (190 mg, 69%); 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.63 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 2.48 (t, J = 7.1 Hz, 2H), 1.70−1.60 (m, 2H), 1.44−1.27 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13 C{1H} NMR (126 MHz, CDCl3) δ 175.7, 151.7, 148.4, 142.0, 129.2, 124.2, 100.7, 80.7, 31.9, 29.2, 29.1 (2C), 27.6, 22.7, 19.5, 14.2; IR (neat) vmax 2922, 2203, 1662 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H21ClNO 278.1306, found 278.1287. Synthesis of 8-Nitro-7-phenylisoquinolin-5-ol (17a). To an ovendried sealed tube were added ynone 15a (0.2 mmol, 48.2 mg) and nitromethane (0.6 mmol, 32 μL) followed by DMSO (3 mL) and K2CO3 (0.6 mmol, 83 mg). The reaction mixture was stirred at 110 °C for 8 h. After the consumption of the starting material (TLC), the reaction was quenched with a saturated solution of aq NH4Cl (10 mL), extracted with EtOAc (3 × 20 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (60% EtOAC/hexane) to obtain the 17a as a pale yellow solid (40 mg, 75%): mp 236−238 °C; 1H NMR (500 MHz, DMSO) δ 9.19 (s, 1H), 8.68 (d, J = 5.7 Hz, 1H), 8.10 (d, J = 5.1 Hz, 1H), 7.54−7.49 (m, 3H), 7.44−7.42 (m, 2H), 7.05 (s, 1H); 13C{1H} NMR (126 MHz, DMSO) δ 155.5, 146.0, 143.6, 137.4, 136.6, 135.5, 129.1, 128.9, 127.7, 126.4, 120.7, 114.9, 112.5; IR (neat) vmax 3056, 2923, 1519, 1357 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C15H11N2O3 267.0764, found 267.0763. Compounds 17b−g were synthesized in a manner similar to that of 17a. 8-Nitro-7-(p-tolyl)isoquinolin-5-ol (17b): yellow solid (37 mg, 66%); mp 242−246 °C; 1H NMR (500 MHz, DMSO) δ 9.14 (s, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.09 (d, J = 5.7 Hz, 1H), 7.33−7.29 (m, 4H), 7.04 (s, 1H), 2.36 (s, 3H); 13C{1H} NMR (126 MHz, DMSO) δ 155.4, 145.9, 143.6, 138.7, 137.4, 135.5, 133.7, 129.8, 127.7, 126.4, 120.8, 115.1, 112.6, 20.9; IR (neat) vmax 3021, 2920, 1521, 1343 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H13N2O3 281.0921, found 281.0923. 7-(4-Methoxyphenyl)-8-nitroisoquinolin-5-ol (17c): yellow solid (38 mg, 64%); mp 218−220 °C; 1H NMR (500 MHz, DMSO) δ 11.80 (bs, 1H), 9.14 (s, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.08 (d, J = 5.7 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.04 (s, 1H), 3.82 (s, 3H); 13C{1H} NMR (126 MHz, DMSO) δ 159.8, 155.1, 145.7, 143.4, 137.3, 134.9, 129.1, 128.5, 126.1, 120.6, 114.9, 114.6, 112.6, 55.3; IR (neat) vmax 2918, 1509, 1342 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C16H13N2O4 297.0870, found 297.0872. 7-(4-Fluorophenyl)-8-nitroisoquinolin-5-ol (17d): yellow solid (35.8 mg, 63%); mp 220−222 °C; 1H NMR (500 MHz, DMSO) δ 9.19 (s, 1H), 8.67 (d, J = 5.7 Hz, 1H), 8.09 (d, J = 5.7 Hz, 1H), 7.51− 7.46 (m, 2H), 7.38−7.34 (m, 2H), 7.03 (s, 1H); 13C{1H} NMR (126 MHz, DMSO) δ 162.4 (d, J = 246.4 Hz), 155.4, 145.9, 143.6, 137.4, 134.6, 132.9 (d, J = 3.2 Hz), 130.0 (d, J = 8.6 Hz), 126.4, 120.6, 116.0 (d, J = 21.9 Hz), 114.9, 112.5; IR (neat) vmax 2919, 1506, 1342 cm−1;

HRMS (ESI) m/z [M + H]+ calcd for C15H10FN2O3 285.0670, found 285.0670. 7-Butyl-8-nitroisoquinolin-5-ol (17e): yellow solid (34.5 mg, 70%); mp 198−200 °C; 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1H), 8.59 (d, J = 5.7 Hz, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.01 (s, 1H), 2.71 (t, J = 7.7 Hz, 2H), 1.62−1.56 (m, 2H), 1.38−1.28 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 155.3, 145.6, 143.1, 137.9, 136.9, 126.0, 120.9, 114.8, 112.3, 32.3, 31.3, 21.9, 13.6; IR (neat) vmax 2922, 1552, 1341 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C13H15N2O3 247.1077, found 247.1076. 8-Nitro-7-pentylisoquinolin-5-ol (17f): yellow solid (35 mg, 67%); mp 196−198 °C; 1H NMR (400 MHz, DMSO) δ 11.72 (s, 1H), 9.09 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.02 (s, 1H), 2.71 (t, J = 7.6 Hz, 2H), 1.66−1.58 (m, 2H), 1.32−1.27 (m, 4H), 0.86 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO) δ 155.2, 145.6, 143.1, 138.0, 136.9, 126.0, 120.9, 114.9, 112.3, 31.6, 30.9, 29.8, 21.8, 13.8; IR (neat) vmax 3273, 2919, 1516, 1341 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H17N2O3 261.1234, found 261.1235. 8-Nitro-7-octylisoquinolin-5-ol (17g): yellow solid (36 mg, 60%); mp 184−186 °C; 1H NMR (500 MHz, DMSO) δ 9.09 (s, 1H), 8.60 (d, J = 5.0 Hz, 1H), 8.02 (d, J = 5.6 Hz, 1H), 7.01 (s, 1H), 2.70 (t, J = 7.6 Hz, 2H), 1.64−1.58 (m, 2H), 1.31−1.22 (m, 10H), 0.84 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (126 MHz, DMSO) δ 155.2, 145.6, 143.1, 138.0, 136.9, 126.0, 120.9, 114.9, 112.3, 31.6, 31.3, 30.2, 28.7, 28.6, 28.5, 22.1, 14.0; IR (neat) vmax 2922, 1511, 1345 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C17H23N2O3 303.1703, found 303.1707.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00950. Control experiments and spectra for all new compounds (PDF) Crystal data of 16g (CCDC 1891839) (CIF) Crystal data of 17a (CCDC 1891498) (CIF) Crystal data of 24 (CCDC 1892026) (CIF) Crystal data of 26 (CCDC 1892021) (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Goverdhan Mehta: 0000-0001-6841-4267 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS M.B. thanks the University Grants Commission in India for the award of Dr. D. S. Kothari’s postdoctoral fellowship. We thank Dr. Ramesh Samineni for interest in this work and Dr. K. Sathish Kumar, Junaid Ali, and G. Anilkumar for help in determining the X-ray crystal structures. G.M. acknowledges the research support from Dr. Reddy’s Laboratories and the award of the Dr. Kallam Anji Reddy Chair Professorship.

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REFERENCES

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