Metal-Free Arylation of Ethyl Acetoacetate with Hypervalent Diaryliodonium Salts: an Immediate Access to Diverse 3-Aryl-4(1H)-Quinolones

Abstract

A clean arylation protocol of ethyl acetoacetate was developed using hypervalent diaryliodonium salts under mild and metal-free conditions. The scope of the reaction, using symmetric and unsymmetric iodonium salts with varying sterics and electronics was examined. Further, this method has been applied for the synthesis of antimalarial compound ELQ-300, which is currently in preclinical development.

INTRODUCTION

Ethyl acetoacetate (EAA) is a versatile and well-established reagent in organic synthesis. EAA's combined electrophilic and nucleophilic nature makes it a convenient reagent for the preparation of a variety of products of different structural complexity. In medicinal chemistry, 2-aryl substituted EAAs provide access to diverse classes of biologically active scaffolds such as important heterocyclics. Various 2-aryl EAA derived compounds were well documented in the literature as antifungal, antibacterial, antitubercular and antitumoral agents.¹ These also served as TNF-α inhibitors, α2C-adrenoreceptor antagonists, DMT1 blockers and HCV NS5B polymerase inhibitors.² In addition, a series of 3-aryl-4(1H)-quinolone compounds, synthesized from corresponding aniline and 2-phenyl EAA, were reported to have excellent low nanomolar activity against malaria.³ Notably, extensive development of this 3-aryl-4(1H)-quinolone chemotype against P. falciparum and P. vivax malaria at all parasite life cycle stages resulted in ELQ-300 (Scheme 1), which recently entered preclinical studies.⁴ Based on the advantage and importance of 2-aryl EAAs as starting materials, suitable and straightforward access to these compounds is required.

Scheme 1.

Synthesis of ELQ-300 via salt route.

Historically, 2-aryl EAAs are prepared using various metal-mediated and metal-free reaction conditions (Figure 1).⁵ In a classical approach, 2-aryl-2-acylacetonitriles are converted to 2-aryl EAAs in two steps under harsh acidic conditions via an imidate intermediate in low to moderate yields.^5a Alternatively, ethyl 2-arylacetate is also acylated under basic conditions with acetyl chloride or acetic anhydride to obtain the target compounds.^5b These transformations, however, are low yielding and produce the deacylated by-product (starting material), which in most cases is inseparable from the EAA product. Finally, under Pd-mediated^2c,5c or Cu-mediated^5d,5e,6 conditions with the appropriate metal ligands, EAA is treated with aryl halides and base to obtain the target compounds at elevated temperatures. In turn, metal-catalyzed reactions suffer from accompanying ligand arylations and product deacylation that is heavily dependent on the nature and quantity of the base used. Moreover, minimal or no usage of expensive metal catalysts is highly advisable in drug discovery because of malfunctions caused by metal contamination at the cellular level.⁷ All of these facts prompted us to develop a protocol in which the 2-aryl EAAs can be obtained easily under mild metal-free reaction conditions.

Figure 1.

Synthesis of 2-aryl EAA.

Hypervalent iodine compounds and diaryliodonium salts in particular have recently captured the attention of synthetic chemists as mild and selective reagents.⁸ One of the biggest advantages of the diaryliodonium salts is the possibility to use metal-free reaction conditions to overcome cost and toxicity of the organometallic chemistry in medicinally interesting compounds.⁹ In recent literature, arylation of hetereoatom nucleophiles like O, N, P etc under various conditions was reported with excellent yields using highly electrophilic hypervalent iodonium salts.¹⁰ Significant amount of research has also been documented on α-arylation of carbonyl compounds such as malonates, ketones, ketoesters, esters using diaryliodonium salts.¹¹ However, most of the attempts were limited to cyclic substrates or α-substituted carbonyl compounds which led to tetra substituted products. To the best of our knowledge, the arylation of EAA with diaryliodonium salts has not been explored by any research group except of a single entry attempt in 1984.¹² Interestingly, a failure effort of arylation of EAA with diphenyliodonium salt was reported in 1999.^10e By the virtue of having one-pot synthetic access to various diaryliodonium salts¹³ and with some of them being commercially available nowadays, it was envisioned to establish a general, simple, and mild arylation protocol of EAA.

RESULTS AND DISCUSSION

Diphenyliodonium tetrafluoroborate 1a was chosen as a test substrate in the optimization of arylation reaction conditions resulting in 2-phenyl EAA in DMF with tBuOK (Table 1). Generally, one equivalent of base with respect to nucleophile was used in all entries in order to avoid double arylation.

Table 1.

Optimization of the arylation reaction^a

Entry	Base (1 eq)	Time (h)	X	Yield (2a) (%)b
1	t-BuOK	18	BF4 (1a)	53
2	Cs2CO3	20	BF4 (1a)	55
3	KOH	24	BF4 (1a)	35
4	K2CO3	28	BF4 (1a)	25
5	NaH	20	BF4 (1a)	40
6	t-BuOK	24	OTf (1b)	45
7	t-BuOK	24	Br (1c)	10
8	t-BuOK	24	PF6 (1d)	60

^aReaction conditions: salt 1 was added to the enolate solution of EAA and ran for tabulated time.

^bIsolated yields in keto and enol form.

To prevent any possible solubility issues with iodonium salts, DMF was the solvent of preference, though most of the salts with BF₄ and OTf anions are soluble in nonpolar solvents. When 1:1 ratio of iodonium salt and EAA was used, the reaction was low yielding because of the formation of double arylated products evident by LC-MS. However, improved yields were obtained when 1:2.5 ratio of iodonium salt and EAA was used. On top, the formation of side products was suppressed according to ¹H-NMR analysis of the crude product. It was found that after reaction completion, the addition of HCl solution in one portion is mandatory to avoid the formation of the deacylated product via a retro-Claisen reaction. Noteworthy, one equivalent of aryl iodide is obtained during course of the reaction and could be reused in case of hardly accessible substrates for diaryliodonium salt formation. Among the different bases screened, Cs₂CO₃ and tBuOK resulted in the best and most reproducible yields (Table 1) in the scale up to 5 grams. Of the two bases, tBuOK was preferred due to its low cost. Subsequently, having these conditions set, the influence of various diphenyliodonium anions on the course of the arylation reaction was examined. Arylations with a diphenyliodonium triflate provided similar yields to the tetrafluoroborate, however, the hexafluorophosphate resulted in 60% yield. The reaction with an iodonium salt with a bromide anion resulted in poor yields possibly due to a combination of competing nucleophilicity of the bromide anion and the low solubility of the bromide salt in DMF as reported before.^10d Although the yield with the PF₆ salt is slightly better than the arylations with BF₄ and OTf anions, it was preferred to proceed with the latter two due to their accessibility and shorter reaction time. Despite initial moderate yields with the unsubstituted diphenyliodonium salt, we wanted to explore the reaction further by probing diverse electron-rich, electron-deficient and sterically hindered electrophiles with the reasonable assumption of getting improved results particularly when using iodonium salts substituted at the aryl rings with electron withdrawing groups.

Firstly, various symmetrical iodonium salts with tetrafluoroborate or triflate anions were prepared and subsequently treated with EAA under optimized conditions.^13–14 The resultant 2-aryl EAAs were then converted to the corresponding 3-aryl-4(1H)-quinolones under modified Conrad-Limpach conditions using 4-chloro-3-methoxyaniline (see the Supporting Information for more details). All the results are summarized in Table 2.

Table 2.

Arylation of EAA with symmetrical salts

Entry	R	Anion 1	Yield 2a (%)	Yield 3a (%)
1	H (1a)	BF4	53 (2a)	60 (3a)
2	2-CH3 (1e)	BF4	73 (2b)	42 (3b)
3	2,4,6-tri CH3 (1f)	OTf	10 (2c)	N.R.(3c)
4	4-CF3 (1g)	BF4	93 (2d)	62 (3d)
5	2-F (1h)	BF4	75 (2e)	54 (3e)
6	4-C1 (1i)	BF4	70 (2f)	68 (3f)
7	4-tBu (1j)	OTf	65 (2g)	67 (3g)
8	2,4-di CH3 (1k)	BF4	60 (2h)	38 (3h)
9	4-COOCH3 (1l)	BF4	90 (2i)	67 (3i)
10	4-OCH3 (1m)	OTf	N.R.b	n/a

^aIsolated yields.

^bno reaction

Generally, arylations of numerous ortho-substituted substrates are problematic in metal-mediated conditions and result in poor yields due to steric bulkiness.^5d Remarkably, the ortho substitution was tolerated well in our case with salts 1h and 1e getting converted to greater than 70% of product signifying an advantage of the selected methodology. In addition, the arylation with 2,4-dimethyl substituted salt 1k delivered 60% yield, whereas dimesityliodonium example 1c resulted in only 10% yield. Noteworthy, compound 2c was obtained in the enol form exclusively, impeding the formation of the enamine during the Conrad-Limpach cyclization. Unsurprisingly, increasing the substitution of the aromatic ring resulted in slightly lower yields in the cyclization step due to steric factors (Table 2).

The arylation of EAA using electron-rich electrophiles like 4-tert-butyl took relatively longer times and revealed marginally lower yields. Moreover, any attempts with 4-methoxy substituted salt 1m did not deliver the required product even after prolonged reaction times. The unreactivity of salt 1m is probably due to reduced electrophilicity of the iodine center. 4-Chloro substituted salt 1i produced the corresponding product in respectable yields under these reaction conditions. Noticeably, salts 1g and 1l, which contain electron-withdrawing groups, behaved excellently, reacting to the corresponding arylated products in less time with yields over 90%. Likely, these results can be linked to an enhanced electrophilicity of the iodine center.

Traditionally, the Conrad-Limpach reaction, which was initially reported in 1887¹⁵, is low-yielding and involves harsh conditions requiring high-boiling solvents like diphenyl ether or polyphosphoric acid.^3,16

In this report, we were able to improve the overall yields, in average by 10%, by using microwave assisted conditions in toluene and reducing the cyclization time to 3 minutes (Table 2). Under classical thermal conditions in Ph₂O, the formation of quinolone is usually accompanied with multiple side products, which interfere with the isolation. Switching the reaction solvent to toluene in a microwave allowed the isolation of analytically pure samples by precipitation with no further need of crystallization.

Next, the chemoselectivity trends were examined with unsymmetrical salts.¹⁷ A few salts with varying sterics and electronics were prepared for this purpose followed by treatment under optimized arylation conditions. The results are summarized in the Table 3.

Table 3.

Arylation of EAA with unsymmetrical salts

Entry	R	Anion 1	Yield 2/2a (%)	Yield 3 (%)
1	mesityl (1n)	OTf	2c/2a 36/0	N.R. (3c)
2	4-NO2 (1o)	BF4	2j/2a 83/0	39 (3j)
3	4-CFs (1p)	OTf	2d/2a 89/0	62 (3k)
4	4-Cl-3-pyridyl (1q)	OTf	2k/2a 50/12	Trace (3l)

Excellent chemoselectivity was observed in the case of phenylmesityl substituted salt 1n, resulting in EAA 2c exclusively in 36% yield. The mesityl group was readily transferred compared to the phenyl group. The latest result was contrary to the one reported in case of sterically hindered aryl group delivery using diethylmalonate as nucleophile.¹⁷ In contrast to the symmetrical salt 1f, the improved yield for this arylation may be due to the steric differences of both rings attached to the iodine center.

During the arylation of salts 1o and 1p, the electron-deficient rings were selectively transferred to produce the products 2j and 2d in excellent yields. Arylation with salt 1q resulted in a 4:1 ratio of the pyridyl ring and phenyl ring products in 62% overall yield. However the Conrad-Limpach cyclization of 2k did not perform well and produced only trace amounts of corresponding 4(1H)-quinolone after several attempts of purification. Arylation pursuits using the 4-anisyl(phenyl) iodonium salt were not successful. The electron-poor rings are preferentially transferred over the electron-rich rings and bulky rings readily transferred over rings lacking in sterics (so-called ortho effect¹⁸).

After having the arylation conditions set, this strategy was applied for the synthesis of antimalarial compound ELQ-300 (Scheme 1).^4,19 The iodonium salt 6 was prepared according to the reported procedure and subsequently treated with 4-iodophenol to obtain the diaryl ether 7 in excellent yield.^9a Next, boronic acid 8 was prepared from aryl iodide 7 and cleanly converted to the appropriate iodonium salt 9. The salt 9 was then treated with EAA under standard arylation conditions providing the corresponding substituted EAA 10 in 52% yield in its pure form of the keto-enol tautomers. This result is better than our previous arylation attempts via the Cu-catalyzed reaction, in which only 30% yield was obtained with the contamination of the inseparable deacylated product (unpublished data). Additionally, one equivalent of the iododiaryl ether 7 was isolated during the reaction, which could be reused to make the salt 9 proving atom-economy of the reaction. Finally, EAA 10 was treated with 4-chloro-3-methoxy aniline under Conrad-Limpach conditions to furnish ELQ-300.

In conclusion, a metal-free arylation of EAA using diaryliodonium salts was broadly studied for the first time. Commercial availability or straightforward accessibility of iodonium salts makes this method convenient and operationally simple. The arylation with symmetrical salts with electron-rich rings delivers good yields with the exception of the reaction with 4-methoxy substituted diaryliodonium salt. Lower yields were also obtained for highly hindered substrates as mesityl analog. Nonetheless, excellent results are obtained with symmetrical salts containing electron-deficient rings. Importantly, the acceptable yields for arylations using ortho-substituted iodonium salts stands in stark contrast to metal-mediated synthetic approaches with similar substrates, which usually do not perform well. Finally, impressive chemoselectivities were also obtained in the case of unsymmetrical salts. Overall this method demonstrated enhanced selectivity and versatility giving straightforward access to medicinally and pharmaceutically interesting EAA derived molecules.

Experimental Section

General Experimental Methods

All reagents and solvents were purchased from commercial sources and used without further purification unless otherwise noted. All reactions were run under an argon atmosphere unless otherwise indicated. Prior to use of solvents in reactions, they were purified by passing the degassed solvents through a column of activated alumina and transferred by an oven-dried syringe or cannula. The identity of all title compounds was verified by via ¹H NMR, ¹³C NMR, and HRMS. The chemical purity of the titled compounds was determined by LC/MS using the following conditions: a LC/MSD with a Phenomenex Kinetex (50 mm × 4.6 mm, 2.6 μm, C18, 100A) reversed phase column; method: 10% (v/v) of acetonitrile (+0.1% FA) in 90% (v/v) of H₂O (+0.1% FA), ramped to 100% acetonitrile (+0.1% FA) over 5.5 min, and holding at 100% acetonitrile for 1 min with a flow rate of 1.3 mL/min, UV detector, 254 nm. The purity of each compound was ≥95% in this analysis. NMR spectra were recorded at ambient temperature on a 400, 500 or 600 MHz NMR spectrometer in the solvent indicated. All ¹H NMR experiments are reported in parts per million (ppm) downfield of TMS and were measured relative to the signals for chloroform (7.26 ppm) and dimethylsulfoxide (2.50 ppm). All ¹³C NMR spectra were reported in ppm relative to the signals for chloroform (77 ppm) and dimethylsulfoxide (39.5 ppm) with ¹H decoupled observation. Data for 1_H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration and coupling constant (Hz), whereas ¹³C-NMR analyses were obtained at 101 or 126 MHz and reported in terms of chemical shift and multiplicity. NMR data was processed by using MestReNova Software ver. 8.1. High resolution mass spectra (HRMS) were performed on an LC/MS Q-TOF system. Microwave experiments were performed on a microwave reactor using sealed reaction vessels and the reaction temperature was monitored with IR sensor. Preparative HPLC was used to separate several compounds by reverse phase (column Eclipse XDB-C18, 5 μM, 9.4×250 mm). Compounds were eluted using a gradient elution of 70/30 to 50/50 A/B over 30 minutes at a flow rate of 5.0 mL/min, where solvent A was 0.1% TFA in water and solvent B was 0.1% TFA in acetonitrile. Analytical thin layer chromatography (TLC) was performed on silica gel 60 F254 pre-coated plates (0.25 mm). and components were visualized by ultraviolet light (254 nm). Silica gel 60. with 230–400 (particle size 40–63 μm) mesh was used for all flash column chromatography.

General procedure for the synthesis of diaryliodonium salts

All the diaryliodonium salts were obtained as described by Bielawski et al.¹³

General procedure for arylation of ethyl acetoacetate (EAA)

A flame dried flask was charged with 10 mmol (1eq) of sublimed potassium tert-butoxide in anhydrous DMF (50 mL) at room temperature under argon. Then 10 mmol (1 eq) of freshly distilled EAA was added to the reaction mixture and stirred for 30 minutes at 0 °C followed by dropwise addition of diaryliodonium salt (4 mmol, 0.4 eq to EAA) in 10 ml of DMF. Reaction was left stirring at room temperature for the time mentioned in the table. After confirming complete consumption of iodonium salt (by LCMS), to the reaction mixture was added 1M HCl in one portion to bring the pH around 5.0. The crude was extracted with diethyl ether until the aqueous layer is devoid of product. Organic layer was dried over sodium sulfate and solvent was removed in vacuo. The product was purified by flash column chromatography (0.5–2% of hexane in ethyl acetate).

General procedure for Conrad-Limpach cyclization

To a round bottom flask was added 4-chloro-3-methoxyaniline (1 mmol), aryl substituted ethyl acetoacetate (1.2 mmol), 10 mol% of AcOH, 5 mL of benzene. The contents were brought to reflux in a Dean-Stark trap with the azeotropic removal of water. After 24–36h the reaction was cooled to room temperature and concentrated in vacuo. A quick chromatography was done to separate any unreacted aniline from the enamine. The resulting enamine was dissolved in 2–3 ml toluene and reacted in microwave at 260 °C for three minutes. The crashed out solid was filtered off and washed with excess amount of diethyl ether and dried. No further purification was needed.

Diphenyliodonium tetrafluoroborate (1a)

Compound 1a was prepared following general procedure for the synthesis of diaryliodonium salts in 85% yield (7.9 g) as off white solid. m.p.: 132–134 °C; Analytic data matches with the previously reported.^{13a 1}H NMR (500 MHz, DMSO) δ 8.28 – 8.23 (m, 4H), 7.69 – 7.64 (m, 2H), 7.55 – 7.51 (m, 4H). ¹³C NMR (126 MHz, DMSO) δ 135.2, 132.1, 131.8, 116.6. ¹⁹F NMR (376 MHz, DMSO) δ −147.72, −147.77. HRMS (ESI-TOF) m/z: [M − BF₄⁻]⁺ 4 calcd for C₁₂H₁₀I 280.9822; found 280.9816.

Di-o-tolyliodonium tetrafluoroborate (1e)

Compound 1e was prepared following general procedure for the synthesis of diaryliodonium salts in 73% yield (5.0 g) as white solid. m.p.: 163–164 °C; Analytic data matches with the previously reported.^{13a 1}H NMR (500 MHz, DMSO) δ 8.32 (d, J = 7.9 Hz, 2H), 7.61 – 7.53 (m, 4H), 7.33 – 7.27 (m, 2H), 2.61 (s, 6H). ¹³CNMR (126 MHz, DMSO) δ 140.6, 137.2, 132.8, 131.6, 129.3, 120.6, 24.0. ¹⁹F NMR (376 MHz, DMSO) δ –147.76, –147.82. HRMS (ESI-TOF) m/z: [M − BF₄⁻]⁺ calcd for C₁₄H₁₄I 309.0135; found 309.01379.

Dimesityliodonium trifluoromethanesulfonate (1f)

Compound 1f was prepared following general procedure for the synthesis of diaryliodonium salts in 58% yield (2.4 g) as white solid. m.p.: 191–192 °C; Analytic data matches with the previously reported.^{13b 1}H NMR (400 MHz, DMSO) δ 7.19 (s, 4H), 2.46 (s, 12H), 2.29 (s, 6H). ¹³C NMR (126 MHz, DMSO) δ 142.7, 141.9, 130.3, 120.7 (q, J = 322.3 Hz), 118.9, 25.3, 20.4. ¹⁹F NMR (376 MHz, DMSO) δ −77.29. HRMS (ESI-TOF) m/z: [M − OTf⁻]⁺ calcd for C₁₈H₂₂I 365.0761; found 365.0766.

Bis(4-(trifluoromethyl)phenyl)iodonium tetrafluoroborate (1g)

Compound 1g was prepared following general procedure for the synthesis of diaryliodonium salts in 63% yield (4.1 g) as white solid. m.p.: 191–192 °C; Analytic data matches with the previously reported.^{13a 1}H NMR (500 MHz, DMSO) δ 8.51 (d, J = 8.3 Hz, 4H), 7.94 (d, J = 8.5 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 136.3, 132.1 (q, J = 32.6 Hz), 128.5 (q, J = 3.6 Hz), 123.4 (q, J = 273.1 Hz), 121.0.¹⁹F NMR (376 MHz, DMSO) δ −61.25, −147.70, −147.75. HRMS (ESI-TOF) m/z: [M − BF₄⁻]⁺ calcd for C₁₄H₈F₆I 416.9569; found 416.9577.

Bis(2-fluorophenyl)iodonium tetrafluoroborate (1h)

Compound 1h was prepared following general procedure for the synthesis of diaryliodonium salts in 60% yield (1.8 g) as white solid. m.p.: 175–176 °C; Analytic data matches with the previously reported.^{13a 1}H NMR (500 MHz, DMSO) δ 8.46 − 8.37 (m, 2H), 7.73 (dd, J = 12.2, 7.6 Hz, 2H), 7.59 (t, J = 7.9 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H). ¹³C NMR (126 MHz, DMSO) δ 160.1, 158.1, 137.1, 136.6 − 135.3 (m), 127.8, 117.0 (d, J = 22.0 Hz), 104.1 (d, J = 23.7 Hz). ¹⁹F NMR (376 MHz, DMSO) δ −97.42 (dt, J = 11.8, 6.1 Hz), −147.74, −147.80. HRMS (ESI-TOF) m/z: [M − BF₄⁻]⁺ calcd for C₁₂H₈F₂I 316.9633; found 316.9634.

Bis(4-chlorophenyl)iodonium tetrafluoroborate (1i)

Compound 1i was prepared following general procedure for the synthesis of diaryliodonium salts in 78% yield (5.0 g) as white solid. m.p.: 167–170 °C; Analytic data matches with the previously reported.^{20 1}H NMR (500 MHz, DMSO) δ 8.26 (d, J = 8.8 Hz, 4H), 7.62 (d, J = 8.8 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 137.5, 137.0, 131.8, 114.7. ¹⁹F NMR (376 MHz, DMSO) δ −147.65, −147.71. HRMS (ESI-TOF) m/z: [M − BF₄⁻]⁺ calcd for C₁₂H₈Cl₂I 348.9042; found 348.9031.

Bis(4-(tert-butyl)phenyl)iodonium trifluoromethanesulfonate (1j)

Compound 1j was prepared following general procedure for the synthesis of diaryliodonium salts in 30% yield (2.1 g) as white solid. m.p.: 153–154 °C; Analytic data matches with the previously reported.^{13b 1}H NMR (500 MHz, DMSO) δ 8.13 (d, J = 8.7 Hz, 4H), 7.53 (d, J = 8.7 Hz, 4H), 1.25 (s, 18H). ¹³C NMR (126 MHz, DMSO) δ 155.2, 135.0, 128.9, 120.8 (q, J = 322.2 Hz), 113.6, 35.0, 30.9. ¹⁹F NMR (376 MHz, DMSO) δ −77.29. HRMS (ESI-TOF) m/z: [M − OTf⁻]⁺ calcd for C₂₀H₂₆I 393.1074; found 393.1086.

Bis(2,4-dimethylphenyl)iodonium trifluoromethanesulfonate (1k)

Compound 1k was prepared following general procedure for the synthesis of diaryliodonium salts in 50% yield (4.1 g) as white solid. m.p.: 169−170 °C; Analytic data matches with the previously reported.^{17 1}H NMR (500 MHz, DMSO) δ 8.15 (d, J = 8.2 Hz, 2H), 7.35 (s, 2H), 7.10 (dd, J = 8.2, 2.0 Hz, 2H), 2.55 (s, 6H), 2.30 (s, 6H). ¹³C NMR (126 MHz, DMSO) δ 143.1, 140.3, 137.0, 132.1, 129.9, 120.7 (q, J = 322.3 Hz), 117.0, 24.7, 20.7. ¹⁹F NMR (376 MHz, DMSO) δ −77.27. HRMS (ESI-TOF) m/z: [M − OTf⁻]⁺ calcd for C₁₆H₁₈I 337.0448; found 337.0449.

Bis(4-(methoxycarbonyl)phenyl)iodonium tetrafluoroborate (1l)

Compound 1l was prepared following general procedure for the synthesis of diaryliodonium salts in 70% yield (3.8 g) as brownish solid. m.p.: 201−203 °C; Analytic data matches with the previously reported.^{21 1}H NMR (500 MHz, DMSO) δ 8.40 (d, J = 8.6 Hz, 4H), 8.03 (d, J = 8.6 Hz, 4H), 3.86 (s, 6H). ¹³C NMR (126 MHz, DMSO) δ 165.1, 135.7, 132.7, 132.0, 121.6, 52.7. ¹⁹F NMR (376 MHz, DMSO) δ −147.74, −147.79. HRMS (ESI-TOF) m/z: [M − BF₄⁻]⁺ calcd for C₁₆H₁₄IO₄ 396.9931; found 396.9932.

Mesityl(phenyl)iodonium trifluoromethanesulfonate (1n)

Compound 1n was prepared following general procedure for the synthesis of diaryliodonium salts. Analytic data matches with the previously reported.^{22 1}H NMR (400 MHz, DMSO) δ 7.98 (dd, J = 7.6, 0.7 Hz, 2H), 7.63 (dd, J = 11.3, 4.1 Hz, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.22 (s, 2H), 2.60 (s, 6H), 2.29 (s, 3H). 13C NMR (101 MHz, DMSO) δ 143.1, 141.6, 134.5, 131.9, 131.8, 129.8, 122.5, 114.5, 26.3, 20.5.

(4-Nitrophenyl)(phenyl)iodonium tetrafluoroborate (1o)

Compound 1o was prepared following general procedure for the synthesis of diaryliodonium salts to give pure diaryliodonium tetrafluoroborate salt in 51% yield (1.8 g) as a grey solid. Analytic data matches with the previously reported.^{13b 1}H NMR (400 MHz, DMSO) δ 8.50 − 8.43 (m, 2H), 8.34 − 8.26 (m, 4H), 7.68 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.9 Hz, 2H). ¹³C NMR (126 MHz, DMSO) δ 149.4, 136.4, 135.4, 132.3, 131.9, 126.2, 123.3, 117.4. HRMS (ESI-TOF) m/z: [M − BF4−]+ calcd for C₁₂H₉INO₂ 325.9672; found 325.9675.

Phenyl(4-(trifluoromethyl)phenyl)iodonium trifluoromethanesulfonate (1p)

Compound 1p was prepared following general procedure for the synthesis of diaryliodonium salts. Analytic data matches with the previously reported.^13b

(6-Chloropyridin-3-yl)(phenyl)iodonium trifluoromethanesulfonate (1q)

Compound 1q was prepared following general procedure 1.1. Analytic data matches with the previously reported.^{13b 1}H NMR (400 MHz, DMSO) δ 9.17 (d, J = 2.3 Hz, 1H), 8.70 (dd, J = 8.5, 2.4 Hz, 1H), 8.28 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H).

Ethyl 3-oxo-2-phenylbutanoate (2a)

Compound 2a was prepared following general procedure for arylation of ethyl acetoacetate in 53% yield (0.53 g) as colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 13.13 (s, 0.3H), 7.41 − 7.27 (m, 4H), 7.18 − 7.13 (m, 1H), 4.69 (s, 0.7H), 4.27 − 4.15 (m, 2H), 2.19 (s, 2H), 1.86 (s, 1H), 1.28 (t, J = 7.1 Hz, 2H), 1.18 (t, J = 7.1Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 201.7, 174.0, 172.7, 168.6, 135.4, 132.8, 131.4, 129.4, 129.0, 128.4, 128.1, 127.0, 104.5, 65.9, 61.8, 60.8, 28.9, 20.0, 14.3, 14.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₄O₃ 207.1016; found 207.1018.

Ethyl 3-oxo-2-(o-tolyl)butanoate (2b)

Compound 2b was prepared following general procedure for arylation of ethyl acetoacetate in 73% yield (4.5 g) as colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 13.07 (s, 0.7H), 7.32 − 7.14 (m, 3H), 7.06 (d, J = 7.3 Hz, 1H), 4.91 (s, 0.3H), 4.30 − 4.06 (m, 2H), 2.35 (s, 1H), 2.18 (s, 1H), 2.17 (s, 2H), 1.75 (s, 2H), 1.28 (t, J = 7.1 Hz, 1H), 1.17 (t, J = 7.1 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 202.1, 173.6, 172.5, 168.9, 138.1, 136.8, 134.7, 131.6, 131.6, 131.0, 129.9, 128.9, 128.3, 127.7, 127.6, 126.7, 125.8, 125.8, 125.8, 125.8, 103.1, 62.4, 61.7, 60.6, 20.0, 19.8, 19.6, 14.4, 14.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₆O₃ 221.1172; found 221.1167.

Ethyl (Z)-3-hydroxy-2-mesitylbut-2-enoate (2c)

Compound 2c was prepared following general procedure for arylation of ethyl acetoacetate in 10% (0.32 g) and 36% (0.41 g) yields with the symmetric and unsymmetric salts respectively as colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 13.07 (s, 1H), 6.89 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 2.09 (s, 6H), 1.67 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 173.3, 172.6, 137.9, 137.0, 131.1, 128.3, 100.9, 60.4, 21.2, 20.2, 19.0, 14.49. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C₁₅H₂₀O₃ 249.1485; found 249.1495.

Ethyl 3-oxo-2-(4-(trifluoromethyl)phenyl)butanoate (2d)

Compound 2d was prepared following general procedure for arylation of ethyl acetoacetate in 93% yield (1.0 g) as colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 13.17 (s, 0.5H), 7.64 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 4.76 (s, 0.5H), 4.29 − 4.14 (m, 2H), 2.23 (s, 1.5H), 1.86 (d, J = 0.7 Hz, 1.5H), 1.28 (t, J = 7.1 Hz, 1.5H), 1.19 (t, J = 7.1 Hz, 1.5H). ¹³C NMR (126 MHz, CDCl₃) δ 200.4, 174.5, 172.2, 168.0, 139.3, 136.5, 131.8, 130.7 (q, J = 32.6 Hz), 130.0, 129.2 (q, J = 32.4 Hz), 125.9 (q, J = 3.8 Hz), 125.1 (q, J = 3.7 Hz), 124.9 (d, J = 272.0 Hz), 124.8 (q, J = 272.0 Hz), 103.6, 65.4, 62.2, 61.0, 29.2, 20.1, 14.3, 14.2. ¹⁹F NMR (376 MHz, CDCl₃) δ −63.05, −63.32. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₃H₁₃F₃O₃ 275.089; found 275.0897.

Ethyl 2-(2-fluorophenyl)-3-oxobutanoate (2e)

Compound 2e was prepared following general procedure for arylation of ethyl acetoacetate in 75% yield (0.7g) as colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 13.21 (s, 0.5H), 7.41 (td, J = 7.6, 1.7 Hz, 0.5H), 7.37 − 7.26 (m, 1H), 7.21 − 7.03 (m, 2.5H), 5.04 (s, 0.5H), 4.31 − 4.10 (m, 2H), 2.24 (s, 1H), 1.86 (s, 2H), 1.28 (t, J = 7.1 Hz, 1H), 1.18 (t, J = 7.1 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 200.8, 174.9, 172.2, 168.1, 160.8 (d, J = 245.6 Hz), 160.6 (d, J = 247.0 Hz), 133.4 (d, J = 2.9 Hz), 130.9 (d, J = 3.2 Hz), 130.2 (d, J = 8.3 Hz), 129.4 (d, J = 8.2 Hz), 124.6 (d, J = 3.8 Hz), 123.8 (d, J = 3.8 Hz), 122.9 (d, J = 16.5 Hz), 120.3 (d, J = 14.6 Hz), 115.7 (d, J = 22.4 Hz), 115.5 (d, J = 22.5 Hz), 97.9, 62.0, 60.9, 57.8, 29.2, 19.8, 14.3, 14.2. ¹⁹F NMR (376 MHz, CDCl₃) δ −113.94 (dd, J = 17.2, 6.4 Hz), −117.92 (dd, J = 18.1, 6.3 Hz). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₃FO₃ 225.0922; found 225.093.

Ethyl 2-(4-chlorophenyl)-3-oxobutanoate (2f)

Compound 2f was prepared following general procedure for arylation of ethyl acetoacetate in 70% yield (0.2 g) as colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 13.10 (s, 0.35H), 7.36 − 7.25 (m, 3H), 7.07 (dd, J = 8.5, 0.6 Hz, 1H), 4.65 (s, 0.65H), 4.18 (m, 2H), 2.18 (s, 2H), 1.83 (s, 1H), 1.25 (t, J = 7.1 Hz, 2H), 1.16 (t, J = 7.1 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 201.0, 174.2, 172.4, 168.2, 134.5, 133.8, 133.0, 132.7, 131.2, 130.8, 129.2, 128.4, 103.4, 65.0, 62.0, 60.9, 29.0, 20.0, 14.3, 14.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₃ClO₃ 241.0626; found 241.063.

Ethyl 2-(4-(tert-butyl)phenyl)-3-oxobutanoate (2g)

Compound 2g was prepared following general procedure for arylation of ethyl acetoacetate in 65% yield (0.5 g) as colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 13.15 (s, 0.25H), 7.39 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.66 (s, 0.75H), 4.28 − 4.15 (m, 2H), 2.18 (s, 2H), 1.86 (s, 1H), 1.34 (s, 3H), 1.31 (s, 6H), 1.28 (t, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 202.0, 174.0, 172.9, 168.9, 151.3, 149.7, 132.1, 130.9, 129.6, 129.0, 126.0, 125.0, 104.3, 65.5, 61.7, 60.7, 34.7, 34.6, 31.5, 31.4, 28.9, 20.1, 14.4, 14.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₂₂O₃ 263.1642; found 263.1632.

Ethyl 2-(2,4-dimethylphenyl)-3-oxobutanoate (2h)

Compound 2h was prepared following general procedure for arylation of ethyl acetoacetate in 60% yield (0.6 g) as colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 13.07 (s,0.9H), 7.19 − 6.88 (m, 3H), 4.86 (s, 0.1H), 4.17 (m, 2H), 2.33 (s, 2.7H), 2.32 (s, 0.3H), 2.30 (s, 0.3H), 2.16 (s, 0.3H), 2.12 (s, 2.7H), 1.75 (s, 2.7H), 1.27 (t, J = 7.1 Hz, 0.3H), 1.17 (t, J = 7.1 Hz, 2.7H). ¹³C NMR (126 MHz, CDCl₃) δ 202.4, 173.7, 172.7, 169.1, 138.1, 137.9, 137.2, 136.6, 131.8, 131.7, 131.4, 130.8, 129.1, 128.8, 127.4, 126.6, 102.9, 62.1, 61.7, 60.6, 21.3, 21.2, 19.9, 19.8, 19.7, 14.5, 14.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₈O₃ 235.1329; found 235.1336.

Methyl 4-(1-ethoxy-1,3-dioxobutan-2-yl)benzoate (2i)

Compound 2i was prepared following general procedure for arylation of ethyl acetoacetate in 70% yield (4.5 g) as colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 13.16 (s, 0.5H), 8.05 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.75 (s, 0.5H), 4.29 – 4.12 (m, 2H), 3.92 (s, 3H), 2.20 (s, 1.5H), 1.86 (s, 1.5H), 1.27 (t, J = 7.2 Hz, 1.5H), 1.17 (t, J = 7.1 Hz, 1.5H). ¹³C NMR (126 MHz, CDCl₃) δ 200.7, 174.3, 172.2, 168.0, 167.1, 166.8, 140.4, 137.6, 131.5, 130.2, 130.2, 129.6, 129.4, 128.8, 103.9, 65.7, 62.1, 61.0, 52.4, 52.3, 29.1, 20.1, 14.23 14.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₄H₁₆O₅ 265.1071; found 265.1073.

Ethyl 2-(4-nitrophenyl)-3-oxobutanoate (2j)

Compound 2j was prepared following general procedure for arylation of ethyl acetoacetate in 82% yield (0.23 g) as yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 13.23 (s, 0.5H), 8.24 (d, J = 8.9 Hz, 1H), 8.20 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 4.83 (s, 0.5H), 4.31 – 4.15 (m, 2H), 2.27 (s, 1.5H), 1.89 (s, 1.5H), 1.29 (t, J = 7.1 Hz, 1.5H), 1.19 (t, J = 7.1 Hz, 1.5H). ¹³C NMR (126 MHz, CDCl₃) δ 199.6, 174.78, 171.7, 167.5, 148.0, 147.0, 142.6, 139.6, 132.4, 130.7, 124.0, 123.4, 103.1, 65.2, 62.4, 61.2, 29.4, 20.2, 14.3, 14.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₁₃NO₅ 252.0867; found 252.0871.

Ethyl 2-(6-chloropyridin-3-yl)-3-oxobutanoate (2k)

Compound 2k was prepared following general procedure for arylation of ethyl acetoacetate in 50% yield (0.12 g) as colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 13.21 (s, 0.6H), 8.30 (d, J = 2.4 Hz, 0.4H), 8.19 (d, J = 2.4 Hz, 0.6H), 7.77 (dd, J = 8.3, 2.5 Hz, 0.4H), 7.47 (dd, J = 8.2, 2.5 Hz, 0.6H), 7.36 (d, J = 8.4 Hz, 0.4H), 7.32 (d, J = 8.2 Hz, 0.6H), 4.73 (s, 0.4 H), 4.21 (m, 2H), 2.28 (s, 1.2H), 1.89 (s, 1.8H), 1.28 (t, J = 7.2 Hz, 1.2H), 1.18 (t, J = 7.1 Hz, 1.8H). ¹³C NMR (101 MHz, CDCl₃) δ 199.4, 175.1, 171.7, 167.3, 151.5, 150.0, 149.8, 141.4, 139.8, 130.1, 127.5, 124.3, 123.7, 99.8, 62.3, 61.9, 61.1, 29.3, 19.9, 14.1, 14.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C₁₁H₁₂ClNO₃ 242.0579; found 242.0570.

6-Chloro-7-methoxy-2-methyl-3-phenylquinolin-4(1H)-one (3a)

Compound 3a was prepared following general procedure for Conrad-Limpach cyclization in 60% yield (0.28 g) as white solid. m.p.: >300°C (decomp); Analytic data matches with the previously reported.^{3 1}H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 7.99 (s, 1H), 7.38 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.06 (s, 1H), 3.96 (s, 3H), 2.19 (s, 3H). ¹³C NMR (101 MHz, DMSO) δ 173.5, 156.7, 146.4, 139.6, 135.9, 130.9, 127.8, 126.5, 126.2, 120.8, 118.8, 117.9, 99.4, 56.4, 18.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₄ClNO₂ 300.0786; found 300.0794.

6-Chloro-7-methoxy-2-methyl-3-(o-tolyl)quinolin-4(1H)-one (3b)

Compound 3b was prepared following general procedure for Conrad-Limpach cyclization in 42% yield (0.33 g) as white solid. m.p.: >300°C (decomp); Analytic data matches with the previously reported.^{23 1}H NMR (500 MHz, DMSO) δ 11.69 (s, 1H), 7.99 (s, 1H), 7.22 (m, 3H), 7.09 (s, 1H), 7.03 (d, J = 7.3 Hz, 1H), 3.96 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H). ¹³C NMR (126 MHz, DMSO) δ 173.2, 156.6, 146.6, 139.7, 137.4, 136.0, 130.8, 129.5, 127.1, 126.1, 125.5, 120.5, 118.6, 117.9, 99.5, 56.4, 19.4, 18.4. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₆ClNO₂ 314.0942; found 314.0943.

6-Chloro-7-methoxy-2-methyl-3-(4-(trifluoromethyl)phenyl)quinolin-4(1H)-one (3d)

Compound 3d was prepared following general procedure for Conrad-Limpach cyclization in 62% yield (2.1 g) as white solid. m.p.: >300°C (decomp); Analytic data matches with the previously reported.^{23 1}H NMR (500 MHz, DMSO) δ 11.75 (s, 1H), 8.00 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H), 3.96 (s, 3H), 2.22 (s, 3H). ¹³C NMR (126 MHz, DMSO) δ 173.2, 156.9, 146.9, 140.4, 139.6, 131.9, 127.1 (q, J = 31.6 Hz), 126.1, 124.6 (q, J = 3.6 Hz), 124.5 (q, J = 271.9 Hz), 119.4, 118.7, 118.3, 99.5, 56.4, 18.9. ¹⁹F NMR (376 MHz, DMSO) δ −60.36. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₃ClF₃NO₂ 368.066; found 368.0662.

6-Chloro-3-(2-fluorophenyl)-7-methoxy-2-methylquinolin-4(1H)-one (3e)

Compound 3e was prepared following general procedure for Conrad-Limpach cyclization in 54% yield (0.35 g) as white solid. m.p.: 309–310 °C; ¹H NMR (500 MHz, DMSO) δ 11.77 (s, 1H), 7.99 (s, 1H), 7.39 (dddd, J = 8.1, 7.2, 5.4, 2.0 Hz, 1H), 7.30 – 7.19 (m, 3H), 7.08 (s, 1H), 3.97 (s, 3H), 2.16 (s, 3H). ¹³C NMR (126 MHz, DMSO) δ 173.5, 160.6 (d, J = 243.5 Hz), 157.3, 147.8, 140.2, 133.8 (d, J = 3.7 Hz), 129.7 (d, J = 8.2 Hz), 126.5, 124.4 (d, J = 3.3 Hz), 123.8 (d, J = 16.8 Hz), 118.8 (d, J = 28.0 Hz), 115.8, 115.6, 115.2, 100.0, 56.9, 18.9. ¹⁹F NMR (376 MHz, DMSO) δ −113.09 (dd, J = 16.1, 6.4 Hz). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₃ClFNO₂ 318.0692; found 318.0698.

6-Chloro-3-(4-chlorophenyl)-7-methoxy-2-methylquinolin-4(1H)-one (3f)

Compound 3f was prepared following general procedure for Conrad-Limpach cyclization in 68% yield (0.48 g) as white solid. m.p.: >300°C (decomp); ¹H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 7.99 (s, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.05 (s, 1H), 3.95 (s, 3H), 2.20 (s, 3H). ¹³C NMR (101 MHz, DMSO) δ 173.3, 156.7, 146.7, 139.6, 134.7, 132.8, 131.2, 127.8, 126.1, 119.4, 118.7, 118.1, 99.5, 56.4, 18.8. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₃Cl₂NO₂ 334.0396; found 334.0405.

3-(4-(tert-butyl)phenyl)-6-chloro-7-methoxy-2-methylquinolin-4(1H)-one (3g)

Compound 3g was prepared following general procedure for Conrad-Limpach cyclization in 67% yield (0.39 g) as white solid. m.p.: >300°C (decomp); ¹H NMR (500 MHz, DMSO) δ 11.64 (s, 1H), 7.99 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 3.96 (s, 3H), 2.20 (s, 3H), 1.32 (s, 9H). ¹³C NMR (126 MHz, DMSO) δ 173.6, 156.7, 148.7, 146.5, 139.6, 132.8, 130.6, 126.2, 124.5, 120.6, 118.7, 117.9, 99.4, 56.4, 34.3, 31.2, 19.0. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₂ClNO₂ 356.1412; found 356.1422.

6-Chloro-3-(2,4-dimethylphenyl)-7-methoxy-2-methylquinolin-4(1H)-one (3h)

Compound 3h was prepared following general procedure for Conrad-Limpach cyclization in 38% yield (0.2 g) as white solid. m.p.: >300°C (decomp); ¹H NMR (500 MHz, DMSO) δ 11.66 (s, 1H), 7.99 (s, 1H), 7.07 (s, 2H), 6.99 (d, J = 7.7 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 3.95 (s, 3H), 2.30 (s, 3H), 2.04 (s, 3H), 1.97 (s, 3H). ¹³C NMR (126 MHz, DMSO) δ 173.2, 156.6, 146.7, 139.7, 137.1, 136.0, 132.9, 130.7, 130.3, 126.1, 120.3, 118.6, 117.9, 99.5, 56.4, 20.8, 19.3, 18.5. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₈ClNO₂ 328.1099; found 328.1104.

Methyl 4-(6-chloro-7-methoxy-2-methyl-4-oxo-1,4-dihydroquinolin-3-yl)benzoate (3i)

Compound 3i was prepared following general procedure for Conrad-Limpach cyclization in 67% yield (0.35 g) as white solid. m.p.: >300°C (decomp); ¹H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 8.00 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.07 (s, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 2.22 (s, 3H). ¹³C NMR (126 MHz, DMSO) δ 173.2, 166.3, 156.8, 146.8, 141.2, 139.6, 131.4, 128.6, 127.8, 126.2, 119.7, 118.7, 118.2, 99.5, 56.4, 52.1, 18.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₆ClNO₄ 358.0841; found 358.0847.

6-Chloro-7-methoxy-2-methyl-3-(4-nitrophenyl)quinolin-4(1H)-one (3j)

Compound 3j was prepared following general procedure for Conrad-Limpach cyclization in 39% yield (0.1 g) as pale yellow solid. ¹H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 8.23 (d, J = 8.7 Hz, 2H), 7.99 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.05 (s, 1H), 3.95 (s, 3H), 2.24 (s, 3H). ¹³C NMR (126 MHz, DMSO) δ 173.0, 156.9, 147.1, 146.0, 143.5, 139.6, 132.4, 126.1, 122.8, 118.7, 118.7, 118.4, 99.6, 56.4, 18.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H13ClN2O4 345.0637; found 345.0646.

6-Chloro-3-(6-chloropyridin-3-yl)-7-methoxy-2-methylquinolin-4(1H)-one (3k)

Compound 3k was prepared following general procedure for Conrad-Limpach cyclization in trace amounts. ¹H NMR (500 MHz, DMSO) δ 11.87 (s, 1H), 8.30 (dd, J = 2.4, 0.4 Hz, 1H), 8.01 (s, 1H), 7.78 (dd, J = 8.2, 2.5 Hz, 1H), 7.55 (dd, J = 8.2, 0.4 Hz, 1H), 7.10 (s, 1H), 3.97 (s, 3H), 2.26 (s, 3H). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C₁₆H₁₂Cl₂N₂O₂ 335.0349; found 335.0336.

Bis(4-(trifluoromethoxy)phenyl)iodonium tetrafluoroborate (6)

Compound 6 was prepared following general procedure for the synthesis of diaryliodonium salts in 65% yield (10.2 g) as white solid. m.p.: 105–108 °C; ¹H NMR (600 MHz, DMSO) δ 8.42 (d, J = 9.1 Hz, 4H), 7.55 (d, J = 8.5 Hz, 4H). ¹³C NMR (151 MHz, DMSO) δ 150.8, 137.8, 124.1, 119.9 (q, J = 258.3 Hz), 114.41.. ¹⁹F NMR (376 MHz, DMSO) δ −120.85, −211.91. HRMS (ESI-TOF) m/z: [M - BF ⁻₄]⁺ calcd for C₁₄H₈F₆IO₂ 448.9468; found 448.9462.

1-Iodo-4-(4-(trifluoromethoxy)phenoxy)benzene (7)

To a suspension of potassium tert-butoxide (1.1 equiv, 6.4 g, 57 mmol) in THF (180 mL) was added 4-iodophenol (1.0 equiv, 52.3 mmol) at 0 °C and the reaction was left to stir at this temperature for 15 min. Diaryliodonium salt (1.1 equiv, 57.2 mmol) solution in dry THF was cannulated and the reaction was stirred in the preheated to 40 °C oil bath for 2 hours (until TLC indicated complete consumption of phenol). The reaction was then quenched with H₂O at 0 °C, the organic phase was separated and the aqueous phase was extracted with diethyl ether (3×200 mL). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude material was purified by flash chromatography (hexanes 100%) to give pure 1-iodo-4-(4-(trifluoromethoxy)phenoxy)benzene in 90% yield (2.7 g) as a colorless liquid.^{9a 1}H NMR (500 MHz, CDCl₃) δ 7.64 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H), 6.78 (d, J = 7.7 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 157.0, 155.3, 145.0 (q, J = 1.9 Hz), 139.0, 122.9 (d, J = 0.6 Hz), 121.2, 120.6 (q, J = 256.8 Hz), 120.0, 86.8. ¹⁹F NMR (376 MHz, CDCl₃) δ −58.77.

(4-(4-(Trifluoromethoxy)phenoxy)phenyl)boronic acid (8)

Compound 8 was prepared as described in literature²⁴ in 90% yield (1.2 g) as white solid. m.p.: 101–103 °C; ¹H NMR (500 MHz, DMSO) δ 8.02 (s, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 9.1 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H). ¹³C NMR (126 MHz, DMSO) δ 158.0, 155.3, 144.8 (q, J = 1.9 Hz), 136.3, 123.0, 120.1, 120.1 (q, J = 255.7 Hz), 117.6. ¹⁹F NMR (376 MHz, DMSO) δ −56.69.

Bis(4-(4-(trifluoromethoxy)phenoxy)phenyl)iodonium tetrafluoroborate (9)

Compound 9 was prepared following modified procedure (for the electron-rich diaryliodonium substrates) of diaryliodonium salts in 56% yield (0.52 g) as white solid. m.p.: 184–186 °C; ¹H NMR (500 MHz, DMSO) δ 8.23 (d, J = 9.1 Hz, 4H), 7.46 (d, J = 8.4 Hz, 4H), 7.23 (d, J = 9.1 Hz, 4H), 7.14 (d, J = 9.1 Hz, 4H). ¹³C NMR (126 MHz, DMSO) δ 160.2, 154.1, 145.3 (q, J = 1.8 Hz), 138.0, 123.7, 122.0, 121.2, 120.5 (q, J = 256.2 Hz), 109.4. ¹⁹F NMR (376 MHz, DMSO) δ −56.66, −147.78, −147.84. HRMS (ESI-TOF) m/z: [M - BF₄⁻]⁺ calcd for C₂₆H₁₆F₆IO₄ 632.9992; found 633.001.

Ethyl 3-oxo-2-(4-(4-(trifluoromethoxy)phenoxy)phenyl)butanoate (10)

Compound 10 was prepared following general procedure for arylation of EAA and purified by preparative HPLC in 52% yield (0.13 g) as colorless oil; ¹H NMR (500 MHz, CDCl₃) δ 13.12 (s, 0.4H), 7.33 (d, J = 8.7 Hz, 1H), 7.22 – 7.17 (m, 2H), 7.13 (d, J = 8.7 Hz, 1H), 7.01 (m, 4H), 4.68 (s, 0.6H), 4.29 – 4.15 (m, 2H), 2.22 (s, 2H), 1.88 (s, 1H), 1.29 (t, J = 7.2 Hz, 2H), 1.20 (t, J = 7.1 Hz, 1H). ¹³C NMR (101 MHz, cdcl₃) δ 201.4, 174.2, 172.7, 168.6, 157.1, 155.9, 155.7, 155.4, 144.9, 144.7, 132.8, 131.1, 130.8, 128.0, 122.8, 122.7, 120.6 (q, J = 255.9 Hz), 120.2, 120.0, 119.1, 118.5, 103.7, 65.0, 61.9, 60.8, 29.0, 20.1, 14.3, 14.2. ¹⁹F NMR (376 MHz, CDCl₃) δ -58.78. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₇F₃O₅ 383.1101; found 383.1101.

6-Chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one (ELQ-300)

Compound ELQ-300 was prepared following general procedure for Conrad-Limpach cyclization in 30% yield (0.4 g), after recrystallization from ethanol and couple of drops of DMSO as off white solid. Analytic data matches with the previously reported.^{4 1}H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 8.00 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 9.1 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 7.06 (s, 1H), 3.96 (s, 3H), 2.23 (s, 3H). ¹³C NMR (101 MHz, DMSO) δ 173.5, 156.7, 155.8, 154.8, 146.6, 143.6, 139.6, 132.7, 131.5, 126.2, 123.0, 120.1 (q, J = 255.7 Hz), 119.9, 119.8, 118.7, 118.3, 118.0, 99.4, 56.4, 18.9. ¹⁹F NMR (376 MHz, DMSO) δ −57.21. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₁₇ClF₃NO₄ 476.0871; found 476.0889.