Electroreductive Intermolecular Coupling of 4-Quinolones with Benzophenones: Synthesis of 2-Substituted 4-Quinolones

Naoki Kise; Yoshie Yoshimura; Tatsuhiro Manto; Toshihiko Sakurai

doi:10.1021/acsomega.9b03342

. 2019 Nov 15;4(22):20080–20093. doi: 10.1021/acsomega.9b03342

Electroreductive Intermolecular Coupling of 4-Quinolones with Benzophenones: Synthesis of 2-Substituted 4-Quinolones

Naoki Kise ^†,‡,^*, Yoshie Yoshimura ^†, Tatsuhiro Manto ^†, Toshihiko Sakurai ^†,‡

PMCID: PMC6882170 PMID: 31788643

Abstract

The electroreductive coupling of 1-alkoxycarbonyl-4-quinolones with benzophenones in the presence of trimethylsilyl chloride gave adducts reacted at the 2-position of 4-quinolones as trimethylsilyl ethers. The adducts were transformed to 2-(diarylhydroxymethyl)-4-quinolones. The electroreduction of 1,3-diethoxycarbonyl-4-quinolones and polyhalogenated 3-alkoxycarbonyl-1-alkyl-4-quinolones with benzophenones also gave adducts reacted at the 2-position of 4-quinolones. On the contrary, the electroreductive coupling of 1,3-diethooxycarbonyl-8-methoxy-4-quinolones occurred at the 4-position of 4-quinolones to give 4-substituted quinolines.

Introduction

4-Quinolone ring has been found in many biologically active compounds¹ and, in particular, is the core skeleton of the quinolone antibiotics (Figure 1).² Therefore, the synthesis of 4-quinolone derivatives has extensively been studied.³ On the other hand, we have reported the electroreductive cross-coupling of heterocycles, such as phthalimides,⁴ indoles,⁵ uracils,⁶ coumarins,⁷ and chromones⁸ with carbonyl compounds. In this context, we attempted the electroreductive cross-coupling of 4-quinolones with carbonyl compounds since this reaction is expected to provide a new synthetic route to 2-subsutituted 4-quinolones.⁹ As far as we know, the reductive cross-coupling of 4-quinolones with carbonyl compounds is hitherto unknown.¹⁰ In this paper, we report the cross-coupling of 1-alkoxycarbonyl-4-quinolones with benzophenones by the electroreduction in the presence of trimethylsilyl chloride (TMSCl) (Scheme 1). The coupled products reacted at the 2-position of 4-quinolones were obtained as trimethylsilyl ethers and transformed to 2-diarylhydroxymethyl-4-quinolones in three steps. The electroreduction of 1,3-diethoxycarbonyl-4-quinolones with benzophenones also gave the coupled products reacted at the 2-position of 4-quinolones, while the same reactions of 1,3-diethoxycarbonyl-8-methoxy-4-quinolones produced the coupled products reacted at the 4-position (Scheme 2). Such a difference of the reacting sites in 1,3-diethoxycarbonyl-4-quinolones can be explained by the density functional theory (DFT) calculations of lowest unoccupied molecular orbital (LUMO) coefficients for these 4-quinolones. Furthermore, the electroreduction of polyhalogenated 3-alkoxycarbonyl-1-alkyl-4-quinolones with benzophenones and subsequent treatment with trifluoroacetic acid (TFA) gave γ-lactones as the coupled products reacted at the 2-position of 4-quinolones (Scheme 3). The γ-lactones could readily be dehydrogenated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The reaction mechanism of the electroreductive coupling was also discussed.

4-Quinolone and biologically active compounds.

Results and Discussion

Electroreductive Coupling of 1-Alkoxycarbonyl-4-quinolones with Benzophenones

First, the electroreduction of 1-methyl-4-quinolone (1a) with benzophenone (2a) (2 equiv) in tetrahydrofuran (THF) containing TMSCl (5 equiv) was carried out (2 F/mol for 2a) according to our already reported method⁴⁻⁸ (Scheme 4). The product coupled at the 2-position of 1a with 2a was obtained as a trimethylsilyl ether 3a in 31% yield and more than 50% of unreacted 1a was recovered. In addition, the product 3a readily returned to the starting materials 1a and 2a by treatment with tetra-n-butylammonium fluoride (TBAF) or 1 M HCl due to fast oxidative cleavage of the desilylated alcohol 4a by air. Based on these results, 1-methoxycarbonyl(Moc)-4-quinolone (1b) was employed in place of 1a to improve the reactivity of the 4-quinolones as an acceptor and the stability of the desilylated alcohols to oxidative cleavage. Expectedly, the corresponding coupled product 3b was obtained by the reaction of 1b with 2a in 69% yield, as shown in Table 1 (run 1). The reaction of other benzophenones 2b–f with 1b afforded the coupled products 3c–g in moderate to good yields (runs 2–6). It was found that benzyloxycarbonyl (Cbz) and t-butyloxycarbonyl (Boc) groups were also effective as activating and protecting groups for 4-quinolones (runs 7–9).

Table 1. Electroreductive Coupling of 1-Alkoxycarbonyl-4-quinolones 1b–d with 2a–f^a.

run	1	X	2	Ar₂C=O	3	% yield^b
1	1b	Moc	2a	Ar = Ph	3b	69
2	1b	Moc	2b	Ar = 4-FC₆H₄	3c	74
3	1b	Moc	2c	xanthone	3d	58
4	1b	Moc	2d	dibenzosuberone	3e	51
5	1b	Moc	2e	dibenzosuberenone	3f	68
6	1b	Moc	2f	9-fluorenone	3g	57
7	1c	Cbz	2a	Ar = Ph	3h	68
8	1c	Cbz	2b	Ar = 4-FC₆H₄	3i	76
9	1d	Boc	2a	Ar = Ph	3j	64

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Electroreduction of 1b–d (1 mmol) and 2a–f (2 mmol) was carried out in 0.3 M Bu₄ClO₄/THF in the presence of TMSCl (5 mmol) using a Pt cathode at a constant current of 0.2 A (400 C).

Isolated yields.

Next, the treatment of 3b–j with TBAF in THF at 25 °C for 10 min gave cyclic carbamates 5a–f by desilylation and following cyclization to 2-oxazolidinones (Table 2). The electroreduction of 1-Moc-3-methyl-4-quinolone (1e) with 2a under the same conditions gave the product 3k as a single stereoisomer (>99% selectivity by ¹H NMR analysis), although the yield was relatively low (36%) (Scheme 5). The stereostructure of 3k was confirmed to be cis by X-ray crystallographic analysis, and this complete cis-selective formation of 3k was in accordance with our previously reported results for the electroreductive coupling of other heterocycles with 2a.⁵⁻⁸ The desilylation of cis-3k with TBAF produced cyclic carbamate 5g as a diastereomeric mixture (cis/trans = 25:75) due to the isomerization of cis-5g to trans-5g.

Table 2. Desilylation of 3b–j with TBAF.

run	3	5	% yield^a
1	3b	5a	89
2	3c	5b	87
3	3d	5c	75
4	3e	5d	88
5	3f	5e	83
6	3g	5f	92
7	3h	5a	85
8	3i	5b	81
9	3j	5a	84

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Isolated yields.

In contrast to 4a (Scheme 4), desilylated alcohol 4b was obtained as a stable solid in 95% yield by the treatment of 3b with 1 M HCl and dioxane (1:1) at 50 °C for 6 h (Scheme 6). Unfortunately, acid-catalyzed detrimethylsiloxylation of 3b and dehydration of 4b did not give 2-diphenylmethyl-4-quinolone 6 but the cyclic carbamate 5a. Incidentally, 4b was treated with NaH in THF to give 5a. Although the efforts to obtain 6 from 3b and 4b resulted in failure, 2-diarylmethyl-4-quinolones 7a and 7b were prepared from N-Cbz-protected 3h and 3i (Scheme 7). The N- and O-deprotections of 3h and 3i proceeded by treatment with HCO₂H/EtOH in the presence of Pd/C at 50 °C for 12 h. The formylation of resultant ammonium salts i with Ac₂O/HCO₂H at 50 °C for 4 h and following treatment of formamides ii in refluxing toluene in the presence of cat. PPTS for 2 h gave 7a and 7b in 25 and 46% total yields, respectively. In the last step, it seems that the dehydration of the β-formamide alcohols ii and subsequent deformylation of 1-formyl-4-quinolones iii took place successively. On the other hand, dehydrogenetion of 5a, 5b, and 5f with DDQ in refluxing dioxane for 3 h afforded 4-quinolones 8a–c in high yields (Table 3). The N,O-deprotection of 8a–c was effected by the treatment with MeONa/MeOH at 25 °C for 1 h to give 2-diarylhydroxymethyl-4-quinolones 9a–c.

Table 3. Dehydrogenation and Subsequent Deprotection of 5a, 5b, and 5f.

run	5	8	% yield^a	9	% yield^a
1	5a	8a	95	9a	82
2	5b	8b	89	9b	96
3	5f	8c	92	9c	70

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Isolated yields.

Electroreductive Coupling of 1,3-Diethoxycarbonyl-4-quinolones with Benzophenones

The electroreduction of 1,3-diethoxycarbonyl-4-quinolone (1f) with 2a was carried out under the same conditions as described in Table 1. Although the coupled product reacted at the 2-position of 1f was obtained as a trimethylsilyl ether, it could not be purified. Therefore, the product was isolated as desilylated alcohol 10a in 63% yield after the treatment of the crude product with 1 M HCl in EtOH at 25 °C for 1 h (Table 4, run 1). The product 10a was found to almost exist as an enol form from the ¹H and ¹³C NMR spectra and X-ray analysis. Other products 10b–e were similarly obtained by the reaction of 1,3-diethoxycarbonyl-4-quinolones 1f–h with 2a and 2b in moderate to good yields (runs 2–5).

Table 4. Electroreductive Coupling of 1,3-Diethoxycarbonyl-4-quinolones 1f–h with 2a and 2b.

run	1	R¹	R²	2	10	% yield^a
1	1f	H	H	2a	10a	63
2	1f	H	H	2b	10b	55
3	1g	MeO	H	2a	10c	61
4	1g	MeO	H	2b	10d	65
5	1h	H	MeO	2a	10e	70

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Isolated yields.

Although the obtained 10a and 10b were readily converted to cyclic carbamates 11a and 11b by the treatment with NaH/THF, the dehydrogenation of 11a and 11b with DDQ/dioxane was very slow (48 h) and brought about 4-quinolones 12a and 12b only in poor yields (Scheme 8). Incidentally, 11a and 11b were obtained as single isomers and the stereostructure of 11a was undoubtedly confirmed to be trans of the keto form by its X-ray analysis.

In contrast, the electroreduction of 1,3-diethoxycarbonyl-8-methoxy-4-quinolone (1i) with 2a under the same conditions produced quinoline 13a (55% yield) as the product coupled at the 4-position of 1i and the product coupled at the 2-position of 1i could not be obtained (Table 5, run 1). In addition, 5,8- and 6,8-dimethoxy-substituted 1,3-diethoxycarbonyl-4-quinolones (1j and 1k) also gave 4-substituted quinolines 13b and 13c by the reaction with 2a, although the yields of 13b and 13c were somewhat low (runs 2 and 3). The desilylation of 13a–c with TBAF-afforded γ-lactones 14a–c (Table 6). The chemical structure of 14a was confirmed by X-ray crystallographic analysis.

Table 5. Electroreductive Coupling of 1,3-Diethoxycarbonyl-4-quinolones 1i–k with 2a.

run	1	R¹	R²	13	% yield^a
1	1i	H	H	13a	55
2	1j	MeO	H	13b	30
3	1k	H	MeO	13c	42

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Isolated yields.

Table 6. Desilylation of 13a–c with TBAF.

run	13	R¹	R²	14	% yield^a
1	13a	H	H	14a	92
2	13b	MeO	H	14b	83
3	13c	H	MeO	14c	98

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Isolated yields.

Electroreductive Coupling of 3-Alkoxycarbonyl-1-alkyl-4-quinolones with Benzophenones

The electroreduction of 3-ethoxycarbonyl-1-methyl-4-quinolone (1l) with 2a was carried out under the same conditions as described in Table 1 (Table 7, run 1). The coupled product iv was formed, even though the yield was low (<25% by ¹H NMR analysis of the crude product). Since the product iv could not be purified, the crude product was desilylated. However, the desilylation of the crude product of iv with TBAF or TFA/CH₂Cl₂ resulted in the oxidative cleavage of desilylated β-amino alcohol v to 1l and 2a in a similar manner to that described in Scheme 4. These miserable results were probably due to the low reactivity of 1l as an acceptor and the high lability of β-amino alcohol v to the oxidative cleavage by air. On the other hand, it is expected that commercially available polyhalogenated 3-alkoxycarbonyl-1-alkyl-4-quinolones 1m and 1n have high reactivity as an acceptor and, in addition, their desilylated β-amino alcohols v have high oxidation resistance owing to the electron-withdrawing halogen substituents. Actually, the electroreduction of 1m and 1n with 2a and 2b and subsequent treatment of the crude products iv with TFA/CH₂Cl₂ at 25 °C for 12 h gave γ-lactones 15b–d (Table 7, runs 2–4). The labile β-amino alcohols v are stabilized by the transformation to the stable γ-lactones 15b–d in the acidic conditions. The dehydrogenation of 15b–d with DDQ immediately proceeded (25 °C, 1 h) to give the corresponding 4-quinolones 16b–d (Table 8).

Table 7. Electroreductive Coupling of 3-Alkoxycarbonyl-4-quinolones 1l–n with 2a and 2b.

run	1	R¹	R²	R³	R⁴	Y	2	15	% yield^a
1	1l	Me	H	H	H	Et	2a	15a	NO^b
2	1m	Et	F	F	F	Et	2a	15b	48
3	1m	Et	F	F	F	Et	2b	15c	30
4	1n	c-Pr	F	Cl	H	Me	2a	15d	51

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Isolated yields.

Not obtained.

Table 8. Dehydrogenation of 15b–d.

run	15	16	% yield^a
1	15b	16b	95
2	15c	16c	72
3	15d	16d	73

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Isolated yields.

Reaction Mechanism of the Electroreductive Coupling 4-Quinolones with Benzophenones

We measured the cyclic voltammetry (CV) of 4-quinolones 1 under the same conditions as already reported CV of benzophenones 2, and these data of first reduction peaks (E_p) are summarized in Table 9. These results show that 2 are generally more reducible than 1, although the differences of E_p values between 1-alkoxycarbonyl-4-quinolones 1b–k, 1m, 1n and 2a–e are relatively small. From these results of CV data and our previously reported results of the reductive coupling of other heterocycles with 2,⁵⁻⁸ the reaction mechanism of the electroreductive coupling of 1 (except for 1i–k) with 2 can be presumed as illustrated in Scheme 9. Initially, carbanion A is generated by the two-electron transfer to 2 and O-silylation with TMSCl. The nucleophilic 1,4-addition of A to the 2-position of 1 and the following O-silylation of resultant enolate anion B produce trimethylsilyl enol ether C. The labile C is readily desilylated to 3 (10′, iv) during workup. Unreacted carbanion A is protonated to give benzhydrol trimethylsilyl ether (vi).

Table 9. E_p values of 1a–n and 2a–f Derived from CV at 25 °C.

1	E_p^a	1	E_p^a	2	E_p^a^,^b
1a	–2.34	1h	–1.89	2a	–1.85
1b	–1.87	1i	–1.76	2b	–1.85
1c	–1.91	1j	–1.88	2c	–1.76
1d	–1.94	1k	–1.82	2d	–1.78
1e	–2.04	1l	–2.20	2e	–1.79
1f	–1.86	1m	–1.95	2f	–1.38
1g	–1.84	1n	–1.87

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First reduction peak (V vs saturated calomel electrode) in CV of 3 mM solution in 0.03 M Bu₄NClO₄/dimethylformamide (DMF) at a Pt cathode at 0.1 V/s.

Reported data in ref (6).

On the contrary, the nucleophilic addition of A occurs at the 4-position of 8-methoxy-substituted 1 (1i–k) and subsequent O-silylation of anion D give trimethylsilyl ether E (Scheme 10). The labile E undergoes rapid aromatization to quinolinium ion F and the following deethoxycarbonylation of F during workup to yield quinoline 13. To elucidate the different reactivity as an acceptor to A between 8-unsubstituted 1,3-diethoxycarbonyl-4-quinolones 1f–h and 8-methoxy substituted ones 1i–k, we calculated the LUMO coefficients and Mulliken charges at the 2 and 4 C carbons of 1f–k at the B3LYP/6-311+G(2d,p) level. As summarized in Table 10, the LUMO coefficients at 2 C are much larger than those at 4 C in 1f–h, while the reverse results are shown in 1i and 1j. Although the LUMO coefficient at 2 C is slightly larger than that at 4 C in 1k, the calculation results practically well explain the difference of the reaction sites to A between 1f–h and 1i–k. It is presumed the reaction site of 1k is determined by more plus charge at 4 C than at 2 C since the difference of the LUMO coefficients between 2 and 4 C is small.

Table 10. Absolute Values of the LUMO Coefficients and Mulliken Charges at the 2 and 4 C Carbons of 1f–k Calculated at the B3LYP/6-311+G(2d,p) Level.

	LUMO coefficients^a		Mulliken charges^b
1	2 C	4 C	2 C	4 C
1f	2.5776	0.4415	–0.0850	0.2114
1g	1.2465	0.4960	0.1293	0.1034
1h	1.1433	0.3899	0.0889	–0.0514
1i	0.3773	1.1864	–0.2315	0.0388
1j	0.8547	1.9946	–0.1921	0.0810
1k	0.0975	0.0320	–0.3270	0.2554

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Larger values are in boldface.

More positive values are in boldface.

Conclusions

The electroreductive intermolecular coupling of 1-alkoxycarbonyl-4-quinolones 1b–e with benzophenones 2a–f in the presence of TMSCl in THF gave the adducts reacted at the 2-position of 1b–e as tetramethylsilane (TMS) ethers 3b–k. The detrimethylsilylation of 3b–k with TBAF in THF afforded cyclic carbamates 5a–g. The TMS ethers 3h and 3i (1-Cbz) were transformed to 2-diarylmethyl-4-quinolones 7a and 7b by hydrogenation, formylation, and dehydration. The cyclic carbamates 5a, 5b, and 5f were transformed to 2-diarylhydroxymethyl-4-quinolones 9a–c by dehydration with DDQ and the following deprotection of the resultant 8a–c with MeONa/MeOH. The electroreductive coupling of 1,3-diethoxycarbonyl-4-quinolones 1f–h with 2a and 2b and subsequent treatment with 1 M HCl/EtOH produced the coupled products 10a–e reacted at the 2-position of 1f–h. In contrast, the electroreductive coupling of 1,3-diethooxycarbonyl-8-methoxy-4-quinolones 1i–k with 2a occurred at the 4-position of 1i–k to give 4-substituted quinolines 13a–c. The electroreduction of polyhalogenated 3-alkoxycarbonyl-1-alkyl-4-quinolones 1m and 1n with 2a and 2b gave the adducts reacted at the 2-position of 1m and 1n, and subsequent treatment of the adducts with TFA/CH₂Cl₂ afforded γ-lactones 15b–d. The treatment of 15b–d with DDQ gave dehydrogenated 4-quinolones 16b–d.

Experimental Section

General Methods

Column chromatography was performed on silica gel 60. THF was freshly distilled from sodium benzophenone ketyl radical. DMF, TMSCl, triethylamine (TEA), and CH₂Cl₂ were distilled from CaH₂.

Starting Materials

4-Quinolones 1a,¹⁰1b,¹¹1c,¹²1d,¹³1f,¹⁴ and 1l(15) were prepared by reported methods. 1-Moc-3-methyl-4-quinolone (1e) was prepared by usual N-methoxycarbonylation¹¹ of 3-methyl-4-quinolone.¹⁰ 1,3-Diethoxycarbonyl-4-quinolones 1g–k were prepared by usual N-ethoxycarbonylation¹⁴ of the corresponding 3-ethoxycarbonyl-4-quinolones.¹⁶ Polyhalogenated 4-quinolones 1m(17) is commercially available and 1n(18) was prepared from its commercially available carboxylic acid by usual esterification with MeI-K₂CO₃/DMF at 50 °C for 12 h.

Methyl 3-Methyl-4-oxoquinoline-1(4H)-carboxylate (1e)

Pale yellow solid; R_f 0.35 (hexane–ethyl acetate, 2:1); mp 94–95 °C; IR [attenuated total reflection (ATR)] 1728, 1647, 1630, 1599 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 2.13 (d, 3H, J = 1.0 Hz), 4.09 (s, 3H), 7.41–7.45 (m, 1H), 7.64–7.68 (m, 1H), 8.31 (d, 1H, J = 1.0 Hz), 8.39–8.42 (m, 1H), 8.64–8.67 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 13.8 (q), 55.0 (q), 119.7 (d), 120.3 (s), 125.0 (d), 125.3 (s), 126.4 (d), 132.4 (d), 135.0 (d), 138.2 (s), 152.0 (s), 179.2 (s); high-resolution mass spectrometry (HRMS) [electrospray ionization (ESI), ion trap] calcd for C₁₂H₁₂NO₃ (M + H⁺) 218.0817, found 218.0807.

Diethyl 6-Methoxy-4-oxoquinoline-1,3(4H)-dicarboxylate (1g)

White solid; R_f 0.45 (hexane–ethyl acetate, 1:1); mp 114–115 °C; IR (ATR) 1759, 1730, 1638, 1607, 1564 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.43 (t, 3H, J = 7.3 Hz), 1.52 (t, 3H, J = 7.3 Hz), 3.92 (s, 3H), 4.42 (q, 2H, J = 7.3 Hz), 4.59 (q, 2H, J = 7.3 Hz), 7.27 (dd, 1H, J = 3.2, 9.5 Hz), 7.86 (d, 1H, J = 3.2 Hz), 8.52 (d, 1H, J = 9.5 Hz), 9.18 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 14.1 (q), 14.2 (q), 55.6 (q), 61.3 (t), 65.8 (t), 107.1 (d), 113.0 (s), 121.4 (d), 122.4 (d), 129.3 (s), 131.4 (s), 143.8 (d), 150.8 (s), 157.5 (s), 164.7 (s), 174.4 (s); HRMS (ESI, ion trap) calcd for C₁₆H₁₈NO₆ (M + H⁺) 320.1134, found 320.1123.

Diethyl 7-Methoxy-4-oxoquinoline-1,3(4H)-dicarboxylate (1h)

White solid; R_f 0.3 (hexane–ethyl acetate, 1:1); mp 120–121 °C; IR (ATR) 1763, 1730, 1616 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.42 (t, 3H, J = 6.9 Hz), 1.52 (t, 3H, J = 7.2 Hz), 3.92 (s, 3H), 4.41 (q, 2H, J = 6.9 Hz), 4.58 (q, 2H, J = 7.2 Hz), 7.04 (dd, 1H, J = 2.3, 9.0 Hz), 8.13 (d, 1H, J = 2.3 Hz), 8.37 (d, 1H, J = 9.0 Hz), 9.14 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 14.1 (q), 14.3 (q), 55.6 (q), 61.3 (t), 65.8 (t), 103.1 (d), 114.1 (s), 114.5 (d), 121.7 (d), 129.1 (s), 139.1 (s), 144.2 (d), 150.9 (s), 163.4 (s), 164.7 (s), 174.2 (s); HRMS (ESI, ion trap) calcd for C₁₆H₁₈NO₆ (M + H⁺) 320.1134, found 320.1122.

Diethyl 8-Methoxy-4-oxoquinoline-1,3(4H)-dicarboxylate (1i)

White solid; R_f 0.35 (hexane–ethyl acetate, 1:1); mp 75–76 °C; IR (ATR) 1765, 1717, 1614, 1601, 1570 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.43 (t, 3H, J = 7.2 Hz), 1.45 (t, 3H, J = 7.2 Hz), 4.11 (s, 3H), 4.41 (q, 2H, J = 7.2 Hz), 4.45 (q, 2H, J = 7.2 Hz), 7.20 (d, 1H, J = 8.2 Hz), 7.58 (t, 1H, J = 8.2 Hz), 7.71 (d, 1H, J = 8.2 Hz), 9.40 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 13.9 (q), 14.0 (q), 56.1 (q), 61.6 (t), 65.6 (t), 110.2 (d), 113.7 (d), 115.3 (s), 123.2 (s), 128.1 (d), 143.0 (s), 149.9 (d), 151.6 (s), 155.0 (s), 155.2 (s), 163.4 (s); HRMS (ESI, ion trap) calcd for C₁₆H₁₈NO₆ (M + H⁺) 320.1134, found 320.1124.

Diethyl 5,8-Dimethoxy-4-oxoquinoline-1,3(4H)-dicarboxylate (1j)

White solid; R_f 0.2 (hexane–ethyl acetate, 1:2); mp 112–114 °C; IR (ATR) 1776, 1701, 1605, 1595 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.42 (t, 3H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.0 Hz), 3.91 (s, 3H), 4.05 (s, 3H), 4.40 (q, 2H, J = 7.2 Hz), 4.44 (q, 2H, J = 7.0 Hz), 6.88 (d, 1H, J = 8.9 Hz), 7.08 (t, 1H, J = 8.9 Hz), 9.34 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 13.6 (q), 13.8 (q), 55.7 (q), 55.9 (q), 61.2 (t), 64.7 (t), 106.7 (d), 109.8 (d), 114.7 (s), 116.3 (s), 143.2 (s), 148.8 (s), 149.0 (d), 150.2 (d), 151.4 (s), 155.0 (s), 163.2 (s); HRMS (ESI, ion trap) calcd for C₁₇H₂₀NO₇ (M + H⁺) 350.1240, found 350.1227.

Diethyl 6,8-Dimethoxy-4-oxoquinoline-1,3(4H)-dicarboxylate (1k)

White solid; R_f 0.35 (hexane–ethyl acetate, 1:1); mp 100–101 °C; IR (ATR) 1767, 1717, 1618, 1599 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.43 (t, 3H, J = 6.9 Hz), 1.45 (t, 3H, J = 7.2 Hz), 3.95 (s, 3H), 4.07 (s, 3H), 4.41 (q, 2H, J = 6.9 Hz), 4.44 (q, 2H, J = 7.2 Hz), 6.82 (d, 1H, J = 2.6 Hz), 6.89 (t, 1H, J = 2.6 Hz), 9.23 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 13.8 (q), 55.4 (q), 56.0 (q), 61.4 (t), 65.5 (t), 90.7 (d), 103.5 (d), 115.5 (s), 123.8 (s), 139.9 (s), 147.1 (d), 151.5 (s), 153.6 (d), 156.1 (s), 159.2 (s), 163.4 (s); HRMS (ESI, ion trap) calcd for C₁₇H₂₀NO₇ (M + H⁺) 350.1240, found 350.1227.

Typical Procedure of Electroreductive Coupling

A 0.3 M solution of Bu₄NClO₄ in THF (15 mL) was placed in a cathodic chamber of a divided cell (40 mL beaker, 3 cm diameter, 6 cm height) equipped with a platinum cathode (5 × 5 cm²), a platinum anode (2 × 1 cm²), and a ceramic cylindrical diaphragm (1.5 cm diameter). A 0.3 M solution of Et₄NOTs in DMF (4 mL) was placed in an anodic chamber (inside the diaphragm). 1-Methoxycarbonyl-4-quinolone (1b) (203 mg, 1.0 mmol), benzophenone (2a) (368 mg, 2.0 mmol), TMSCl (0.64 mL, 5.0 mmol), and TEA (0.70 mL, 5.0 mmol) were added to the cathodic chamber. After 400 C of electricity (2 F/mol for 2a) was passed at a constant current of 200 mA at 25 °C under nitrogen atmosphere, the catholyte was evaporated in vacuo. The residue was dissolved in diethyl ether (20 mL) and insoluble solid was filtered off. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 3b (317 mg) in 69% yield.

2-(Diphenyl((trimethylsilyl)oxy)methyl)-1-methyl-2,3-dihydroquinolin-4(1H)-one (3a)

Yellow solid (129 mg); R_f 0.35 (hexane–ethyl acetate, 5:1); mp 159–160 °C; IR (ATR) 1670, 1601 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.27 (s, 9H), 2.92 (d, 1H, J = 17.2 Hz), 2.99 (s, 3H), 3.06 (dd, 1H, J = 8.5, 17.2 Hz), 4.53 (d, 1H, J = 8.5 Hz), 6.36–6.41 (m, 2H), 7.09–7.14 (m, 3H), 7.19–7.23 (m, 1H), 7.27–7.33 (m, 5H), 7.34–7.40 (m, 3H); ¹³C NMR (125 Hz, CDCl₃) δ 1.5 (q), 39.0 (t), 42.4 (q), 69.1 (d), 85.9 (s), 112.0 (d), 114.7 (d), 118.7 (s), 126.6 (d), 127.2 (d), 127.6 (d), 127.9 (d), 128.0 (d), 129.2 (d), 134.9 (d), 140.7 (s),141.7 (s), 150.8 (s), 192.3 (s); HRMS (ESI, ion trap) calcd for C₂₆H₃₀NO₂Si (M + H⁺) 416.2046, found 416.2026.

Methyl 2-(Diphenyl((trimethylsilyl)oxy)methyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3b)

Colorless paste (317 mg); R_f 0.25 (hexane–ethyl acetate, 5:1); IR (ATR) 1707, 1686, 1601 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.36 (s, 9H), 3.09 (d, 1H, J = 17.5 Hz), 3.16 (dd, 1H, J = 6.7, 17.5 Hz), 3.60 (s, 3H), 5.88 (brs, 1H), 7.08–7.13 (m, 3H), 7.17–7.30 (m, 9H), 7.39–7.44 (m, 1H), 7.79–7.83 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 1.3 (q), 40.8 (t), 53.2 (q), 61.3 (d), 85.7 (s), 123.7 (d), 125.2 (d), 126.1 (d), 126.5 (s), 127.0 (d), 127.4 (d), 127.8 (d), 128.0 (d), 128.5 (d), 133.0 (d), 141.7 (s), 143.4 (s), 143.5 (s), 154.6 (s), 192.9 (s); HRMS (ESI, ion trap) calcd for C₂₇H₃₀NO₄Si (M + H⁺) 460.1944, found 467.1934.

Methyl 2-(Bis(4-fluorophenyl)((trimethylsilyl)oxy)methyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3c)

Colorless paste (367 mg); R_f 0.25 (hexane–ethyl acetate, 5:1); IR (ATR) 1705, 1684, 1603 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.34 (s, 9H), 3.08 (d, 1H, J = 17.8 Hz), 3.17 (dd, 1H, J = 6.9, 17.8 Hz), 3.66 (s, 3H), 5.85 (d, 1H, J = 6.9 Hz), 6.85–6.90 (m, 2H), 6.95–7.00 (m, 2H), 7.03–7.08 (m, 2H), 7.09–7.13 (m, 1H), 7.22–7.27 (m, 3H), 7.39–7.44 (m, 1H), 7.76–7.79 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 1.2 (q), 40.5 (t), 53.3 (q), 61.2 (d), 84.5 (s), 113.9 (d, J_CCF = 21.0 Hz), 114.9 (d, J_CCCF = 21.6 Hz), 123.9 (d), 125.2 (d), 126.1 (d), 126.4 (s), 129.7 (d, J_CCCF = 7.8 Hz), 130.3 (d, J_CCCF = 8.4 Hz), 133.1 (d), 139.1 (s), 141.4 (s), 154.7 (s), 161.9 (s, J_CF = 247.1 Hz), 162.0 (s, J_CF = 248.3 Hz), 192.4 (s); HRMS (ESI, ion trap) calcd for C₂₇H₂₈F₂NO₄Si (M + H⁺) 496.1756, found 496.1744.

Methyl 4-Oxo-2-(9-((trimethylsilyl)oxy)-9H-xanthen-9-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (3d)

Colorless paste (275 mg); R_f 0.3 (hexane–ethyl acetate, 5:1); IR (ATR) 1717, 1688, 1601 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.34 (s, 9H), 2.84 (dd, 1H, J = 6.7, 17.9 Hz), 3.26 (d, 1H, J = 17.9 Hz), 3.35 (brs, 3H), 4.77 (d, 1H, J = 6.7 Hz), 6.95–6.99 (m, 1H), 7.04–7.11 (m, 2H), 7.15–7.18 (m, 1H), 7.18–7.25 (m, 2H), 7.27–7.30 (m, 1H), 7.34–7.38 (m, 1H), 7.48–7.53 (m, 1H), 7.60–7.63 (m, 1H), 7.76–7.90 (m, 2H); ¹³C NMR (125 Hz, CDCl₃) δ 1.3 (q), 37.4 (t), 52.9 (q), 63.0 (d), 76.2 (s), 115.9 (d), 116.5 (d), 122.3 (d), 122.8 (d), 123.4 (d), 123.7 (d), 124.6 (s), 125.1 (s), 125.6 (d), 126.4 (s), 127.3 (d), 128.1 (d), 129.3 (d), 129.4 (d), 133.5 (d), 142.1 (s), 150.2 (s), 154.1 (s), 193.0 (s); HRMS (ESI, ion trap) calcd for C₂₇H₂₈NO₅Si (M + H⁺) 474.1737, found 474.1720.

Methyl 4-Oxo-2-(5-((trimethylsilyl)oxy)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (3e)

White solid (248 mg); R_f 0.3 (hexane–ethyl acetate, 5:1); mp 161–162 °C; IR (ATR) 1715, 1690, 1601 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.38 (s, 9H), 2.62 (dd, 1H, J = 2.0, 17.2 Hz), 2.69 (dd, 1H, J = 6.3, 17.2 Hz), 2.89–3.02 (m, 2H), 3.20 (dd, 1H, J = 7.3, 15.8 Hz), 3.43 (brs, 3H), 3.53 (t, 1H, J = 12.9 Hz), 5.25 (d, 1H, J = 6.3 Hz), 7.03–7.08 (m, 1H), 7.09–7.23 (m, 4H), 7.25–7.29 (m, 1H), 7.30–7.34 (m, 1H), 7.40–7.44 (m, 1H), 7.55–7.61 (m, 1H), 7.76–7.78 (m, 1H), 7.81–7.92 (m, 1H), 8.03–8.09 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 1.5 (q), 34.8 (t), 36.4 (t), 38.4 (t), 52.8 (q), 63.1 (d), 89.5 (s), 123.2 (d), 123.8 (d), 124.3 (d), 125.6 (d), 125.9 (d), 126.4 (s), 127.5 (d), 128.2 (d), 129.8 (d), 130.5 (d), 131.9 (d), 133.3 (d), 139.5 (s), 139.8 (s), 140.9 (s), 141.0 (s), 142.8 (s), 154.5 (s), 192.8 (s); HRMS (ESI, ion trap) calcd for C₂₉H₃₂NO₄Si (M + H⁺) 486.2101, found 486.2081.

Methyl 4-Oxo-2-(5-((trimethylsilyl)oxy)-5H-dibenzo[a,d][7]annulen-5-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (3f)

Colorless paste (329 mg); R_f 0.25 (hexane–ethyl acetate, 5:1); mp 181–183 °C; IR (ATR) 1717, 1680, 1597 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.07 (s, 9H), 2.32 (d, 1H, J = 18.0 Hz), 2.58 (dd, 1H, J = 7.3, 18.0 Hz), 3.48 (s, 3H), 5.47 (d, 1H, J = 7.3 Hz), 6.85 (d, 1H, J = 11.9 Hz), 6.94 (d, 1H, J = 11.9 Hz), 7.16–7.20 (m, 1H), 7.27–7.51 (m, 9H), 7.77–7.80 (m, 1H), 8.00–8.02 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 2.6 (q), 37.8 (t), 52.7 (q), 55.9 (d), 90.2 (s), 123.6 (d), 124.9 (d), 125.6 (d), 127.0 (d), 127.2 (s), 127.6 (d), 127.8 (d), 127.9 (d), 128.2 (d), 130.1 (d), 130.3 (d), 131.1 (d), 132.9 (s), 133.2 (d), 133.4 (s), 139.5 (s), 140.2 (s), 142.8 (s), 154.5 (s), 193.1 (s); HRMS (ESI, ion trap) calcd for C₂₉H₃₀NO₄Si (M + H⁺) 484.1944, found 484.1924.

Methyl 4-Oxo-2-(9-((trimethylsilyl)oxy)-9H-fluoren-9-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (3g)

Colorless paste (261 mg); R_f 0.45 (hexane–ethyl acetate, 2:1); IR (ATR) 1719, 1690, 1599 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.58 (s, 9H), 3.06 (dd, 1H, J = 6.9, 17.8 Hz), 3.42 (brs, 3H), 3.52 (dd, 1H, J = 1.6, 17.8 Hz), 4.73 (d, 1H, J = 1.6 Hz), 7.12–7.16 (m, 1H), 7.18–7.22 (m, 1H), 7.27–7.34 (m, 3H), 7.37–7.41 (m, 1H), 7.51–7.57 (m, 3H), 7.60–7.63 (m, 1H), 7.78–7.98 (m, 2H); ¹³C NMR (125 Hz, CDCl₃) δ 0.5 (q), 38.8 (t), 52.9 (q), 61.3 (d), 87.8 (s), 120.1 (d), 120.2 (d), 123.4 (d), 125.1 (d), 125.3 (d), 125.8 (d), 126.7 (s), 126.9 (d), 127.1 (d), 129.1 (d), 129.2 (d), 133.4 (d), 139.2 (s), 139.4 (s), 142.4 (s), 146.6 (s), 146.7 (s), 154.4 (s), 193.0 (s); HRMS (ESI, ion trap) calcd for C₂₇H₂₈NO₂Si (M + H⁺) 458.1788, found 458.1769.

Benzyl 2-(Diphenyl((trimethylsilyl)oxy)methyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3h)

White solid (364 mg); R_f 0.5 (hexane–ethyl acetate, 5:1); mp 124–126 °C; IR (ATR) 1705, 1688, 1597 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.40 (s, 9H), 2.96–3.16 (m, 2H), 4.90 (d, 1H, J = 12.2 Hz), 5.13 (d, 1H, J = 12.2 Hz), 5.85 (brs, 1H), 7.08–7.17 (m, 7H), 7.19–7.34 (m, 10H), 7.38–7.45 (m, 1H), 7.84–7.88 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 1.3 (q), 40.7 (t), 61.8 (d), 68.0 (t), 86.0 (s), 123.8 (d), 125.2 (brd), 126.1 (d), 126.6 (s), 127.1 (d), 127.4 (d), 127.8 (d), 127.9 (d), 128.0 (d), 128.1 (d), 128.2 (d), 128.3 (d), 128.4 (d), 128.5 (d), 133.0 (d), 135.6 (s), 141.7 (s), 143.3 (s), 154.1 (s), 192.8 (s); HRMS (ESI, ion trap) calcd for C₃₃H₃₄NO₄Si (M + H⁺) 536.2257, found 536.2249.

Benzyl 2-(Bis(4-fluorophenyl)((trimethylsilyl)oxy)methyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3i)

Colorless paste (434 mg); R_f 0.45 (hexane–ethyl acetate, 5:1); IR (ATR) 1686, 1601 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.38 (s, 9H), 3.01 (d, 1H, J = 17.4 Hz), 3.13 (dd, 1H, J = 6.4, 17.4 Hz), 4.97 (d, 1H, J = 12.1 Hz), 5.17 (d, 1H, J = 12.1 Hz), 5.82 (brs, 1H), 6.76–6.81 (m, 2H), 6.94–7.04 (m, 4H), 7.10–7.15 (m, 1H), 7.15–7.19 (m, 2H), 7.19–7.24 (m, 2H), 7.32–7.44 (m, 4H), 7.80–7.85 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 1.1 (q), 40.4 (t), 61.5 (d), 68.1 (t), 84.8 (s), 113.8 (d, J_CCF = 20.4 Hz), 114.8 (d, J_CCF = 21.6 Hz), 123.9 (d), 125.1 (brd), 126.1 (d), 126.4 (s), 127.9 (d), 128.2 (d), 128.4 (d), 129.6 (d, J_CCCF = 8.4 Hz), 130.1 (d, J_CCCF = 8.4 Hz), 133.1 (d), 135.4 (s), 138.8 (s), 138.9 (s), 141.3 (s), 153.9 (s), 161.8 (s, J = 247.1 Hz), 161.9 (s, J = 248.3 Hz), 192.4 (s); HRMS (ESI, ion trap) calcd for C₃₃H₃₁F₂NO₄Si (M + H⁺) 572.2069, found 572.2055.

t-Butyl 2-(Diphenyl((trimethylsilyl)oxy)methyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3j)

Colorless paste (321 mg); R_f 0.25 (hexane–ethyl acetate, 10:1); IR (ATR) 1686, 1601 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.41 (s, 9H), 1.29 (s, 9H), 2.82–3.14 (m, 2H), 5.62–5.81 (m, 1H), 7.09–7.13 (m, 1H), 7.15–7.24 (m, 5H), 7.28–7.38 (m, 6H), 7.40–7.48 (m, 1H), 7.86–7.92(m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 1.2 (q), 27.8 (q), 40.3 (t), 61.4 (d), 81.6 (s), 86.4 (s), 123.1 (d), 125.0 (s), 125.9 (d), 126.4 (s), 127.0 (d), 127.2 (d), 127.6 (d), 127.9 (d), 128.2 (d), 132.8 (s), 142.2 (s), 143.2 (s), 152.7 (s), 193.0 (s); HRMS (ESI, ion trap) calcd for C₂₇H₃₆NO₄Si (M + H⁺) 502.2414, found 502.2404.

Methyl (2S,3S)-2-(Diphenyl((trimethylsilyl)oxy)methyl)-3-methyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (cis-3k)

White solid (171 mg); R_f 0.5 (hexane–ethyl acetate, 5:1); mp 180–181 °C; IR (ATR) 1697, 1684, 1599 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.33 (s, 9H), 0.91 (d, 3H, J = 6.3 Hz), 3.24–3.31 (m, 1H), 3.56 (s, 3H), 5.89 (brs, 1H), 7.08–7.21 (m, 6H), 7.29–7.39 (m, 3H), 7.45–7.51 (m, 3H), 7.75 (brs, 1H), 7.94–7.98 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 1.6 (q), 12.6 (q), 46.0 (d), 53.1 (q), 68.1 (d), 86.5 (s), 123.3 (d), 123.5 (brs), 125.1 (s), 126.3 (d), 126.8 (d), 127.4 (d), 127.5 (d), 128.3 (d), 128.5 (d), 133.0 (s), 142.2 (s), 142.8 (s), 143.3 (s), 154.5 (s), 194.5 (s); HRMS (ESI, ion trap) calcd for C₂₈H₃₂NO₄Si (M + H⁺) 474.2101, found 474.2078.

Ethyl 4-(Diphenyl((trimethylsilyl)oxy)methyl)-8-methoxyquinoline-3-carboxylate (13a)

White solid (267 mg); R_f 0.4 (hexane–ethyl acetate, 1:1); mp 108–109 °C; IR (ATR) 1715, 1609, 1568 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.20 (s, 9H), 0.89 (t, 3H, J = 7.0 Hz), 3.89–4.02 (m, 2H), 4.06 (s, 3H), 6.90 (d, 1H, J = 8.5 Hz), 7.04 (t, 1H, J = 8.5 Hz), 7.25–7.34 (m, 11H), 8.93 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 1.7 (q), 13.3 (q), 56.0 (q), 60.8 (t), 85.7 (s), 107.0 (d), 120.9 (s), 125.4 (d), 127.4 (s), 127.7 (d), 128.0 (d), 128.4 (s), 128.7 (d), 141.5 (s), 144.7 (s), 147.9 (d), 151.7 (s), 155.2 (s), 169.1 (s); HRMS (ESI, ion trap) calcd for C₂₉H₃₁NO₄Si (M + H⁺) 486.2101, found 486.2094.

Ethyl 4-(Diphenyl((trimethylsilyl)oxy)methyl)-5,8-dimethoxyquinoline-3-carboxylate (13b)

Yellow solid (155 mg); R_f 0.55 (hexane–ethyl acetate, 1:1); mp 194–196 °C; IR (ATR) 1713, 1612 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.33 (s, 9H), 0.56 (t, 3H, J = 7.3 Hz), 2.72 (s, 3H), 3.88 (q, 2H, J = 7.3 Hz), 4.06 (s, 3H), 6.33 (d, 1H, J = 8.6 Hz), 6.90 (d, 1H, J = 8.6 Hz), 7.13–7.22 (m, 10H), 9.03 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 1.4 (q), 12.7 (q), 52.8 (q), 56.2 (q), 60.9 (t), 87.8 (s), 104.7 (d), 107.7 (d), 121.1 (s), 126.6 (d), 126.8 (d), 128.7 (d), 130.3 (s), 141.2 (s), 145.4 (s), 147.7 (s), 148.9 (d), 149.3 (s), 154.1 (s), 169.2 (s); HRMS (ESI, ion trap) calcd for C₃₀H₃₄NO₅Si (M + H⁺) 516.2206, found 516.2190.

Ethyl 4-(Diphenyl((trimethylsilyl)oxy)methyl)-6,8-dimethoxyquinoline-3-carboxylate (13c)

White solid (217 mg); R_f 0.55 (hexane–ethyl acetate, 1:1); mp 178–180 °C; IR (ATR) 1721, 1624, 1576 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ −0.18 (s, 9H), 0.85 (t, 3H, J = 7.2 Hz), 3.10 (brs, 3H), 3.92–4.00 (m, 2H), 4.02 (s, 3H), 6.23 (brs, 1H), 6.56 (d, 1H, J = 2.7 Hz), 7.26–7.32 (m, 10H), 8.79 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 1.8 (q), 13.3 (q), 54.9 (q), 56.1 (q), 60.6 (t), 85.6 (s), 99.5 (d), 100.8 (d), 127.7 (d), 128.0 (d), 128.6 (d), 138.4 (s), 145.0 (s), 145.5 (d), 147.7 (s), 150.0 (s), 156.1 (s), 156.7 (s), 169.2 (s); HRMS (ESI, ion trap) calcd for C₃₀H₃₄NO₅Si (M + H⁺) 516.2206, found 516.2184.

Desilylation of 3 with TBAF

To a solution of 3b (230 mg, 0.5 mmol) in THF (10 mL) was added 1 M TBAF in THF (0.5 mL, 0.5 mmol) at 25 °C, and the solution was stirred for 10 min. After addition of AcOH (30 mg, 0.5 mmol), the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 5a (155 mg) in 87% yield.

3,3-Diphenyl-3a,4-dihydro-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (5a)

White solid (155 mg); R_f 0.3 (hexane–ethyl acetate, 5:1); mp 118–119 °C; IR (ATR) 1761, 1684, 1599 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 2.24 (dd, 1H, J = 15.0, 16.5 Hz), 2.75 (dd, 1H, J = 3.4, 16.5 Hz), 5.23 (dd, 1H, J = 3.4, 15.0 Hz), 7.17–7.25 (m, 3H), 7.31–7.50 (m, 8H), 7.60–7.65 (m, 1H), 7.94–7.98 (m, 1H), 8.46–8.50 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 41.6 (t), 62.1 (d), 86.0 (s), 118.2 (d), 121.4 (s), 124.0 (d), 125.9 (d), 126.4 (d), 127.5 (d), 128.7 (d), 128.8 (d), 129.0 (d), 135.8 (d), 138.2 (s), 140.0 (s), 140.7 (s), 152.8 (s), 191.1 (s); HRMS (ESI, ion trap) calcd for C₂₃H₁₈NO₃ (M + H⁺) 356.1287, found 356.1284.

3,3-Bis(4-fluorophenyl)-3a,4-dihydro-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (5b)

Colorless paste (158 mg); R_f 0.35 (hexane–ethyl acetate, 5:1); IR (ATR) 1757, 1684, 1601 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 2.23 (dd, 1H, J = 14.9, 16.0 Hz), 2.71 (dd, 1H, J = 3.4, 16.0 Hz), 5.19 (dd, 1H, J = 3.4, 14.9 Hz), 7.03–7.11 (m, 2H), 7.11–7.24 (m, 5H), 7.41–7.50 (m, 2H), 7.59–7.66 (m, 1H), 7.92–7.98 (m, 1H), 8.41–8.47 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 41.5 (t), 62.2 (d), 85.2 (s), 115.6 (d, J_CCF = 21.6 Hz), 116.0 (d, J_CCF = 21.6 Hz), 118.3 (d), 121.4 (s), 124.2 (d), 127.6 (d), 127.8 (d, J_CCCF = 8.4 Hz), 128.4 (d, J_CCCF = 7.8 Hz), 134.0 (s, J_CCCCF = 3.0 Hz), 135.9 (d), 136.5 (s, J_CCCCF = 3.0 Hz), 139.8 (s), 152.4 (s), 162.7 (s, J_CF = 250.7 Hz), 162.8 (s, J = 249.5 Hz), 190.6 (s); HRMS (ESI, ion trap) calcd for C₂₃H₁₆F₂NO₃ (M + H⁺) 392.1098, found 392.1083.

3a,4-Dihydro-1H,5H-spiro[oxazolo[3,4-a]quinoline-3,9′-xanthene]-1,5-dione (5c)

White solid (107 mg); R_f 0.35 (hexane–ethyl acetate, 5:1); mp 194–196 °C; IR (ATR) 1753, 1688, 1599 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 2.12 (dd, 1H, J = 14.8, 16.3 Hz), 2.31 (dd, 1H, J = 3.7, 16.3 Hz), 4.54 (dd, 1H, J = 3.7, 14.8 Hz), 7.18–7.22 (m, 1H), 7.23–7.32 (m, 4H), 7.43–7.49 (m, 2H), 7.51–7.54 (m, 1H), 7.65–7.70 (m, 1H), 7.71–7.74 (m, 1H), 7.90–7.94 (m, 1H), 8.64 (d, 1H, J = 8.3 Hz); ¹³C NMR (125 Hz, CDCl₃) δ 38.4 (t), 67.0 (d), 77.2 (s), 116.9 (d), 117.4 (d), 117.5 (s), 117.6 (d), 120.5 (s), 121.5 (s), 123.9 (d), 124.1 (d), 124.5 (d), 125.8 (d), 126.2 (d), 127.7 (d), 130.6 (d), 130.9 (d), 135.9 (d), 139.4 (s), 150.3 (s), 150.5 (s), 152.9 (s), 190.6 (s); HRMS (ESI, ion trap) calcd for C₂₃H₁₆NO₄ (M + H⁺) 370.1079, found 370.1064.

3a′,4′,10,11-Tetrahydro-1′H,5′H-spiro[dibenzo[a,d][7]annulene-5,3′-oxazolo[3,4-a]quinoline]-1′,5′-dione (5d)

Yellow paste (97 mg); R_f 0.3 (hexane–ethyl acetate, 5:1); IR (ATR) 1759, 1684, 1599 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 2.46 (dd, 1H, J = 14.5, 16.5 Hz), 2.58 (dd, 1H, J = 3.3, 16.5 Hz), 2.95–3.02 (m, 1H), 3.03–3.12 (m, 1H), 3.24–3.36 (m, 2H), 4.94 (dd, 1H, J = 3.3, 14.5 Hz), 7.16–7.35 (m, 7H), 7.57–7.63 (m, 1H), 7.81–7.87 (m, 2H), 7.89–7.97 (m, 2H); ¹³C NMR (125 Hz, CDCl₃) δ 31.9 (t), 33.4 (t), 42.5 (t), 66.6 (d), 84.6 (s), 121.1 (d), 123.3 (s), 124.4 (d), 124.8 (d), 126.1 (d), 126.7 (d), 127.0 (d), 127.2 (d), 128.9 (d), 129.0 (d), 130.3 (d), 131.8 (d), 133.9 (s), 135.5 (d), 137.1 (s), 137.5 (s), 139.4 (s), 141.3 (s), 152.3 (s), 191.4 (s); HRMS (ESI, ion trap) calcd for C₂₅H₂₀NO₃ (M + H⁺) 382.1443, found 382.1427.

3a′,4′-Dihydro-1′H,5′H-spiro[dibenzo[a,d][7]annulene-5,3′-oxazolo[3,4-a]quinoline]-1′,5′-dione (5e)

Colorless paste (129 mg); R_f 0.35 (hexane–ethyl acetate, 5:1); mp 242–244 °C; IR (ATR) 1775, 1767, 1688, 1599 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 2.24–2.31 (m, 2H), 4.64–4.71 (m, 1H), 7.07 (s, 2H), 7.15–7.20 (m, 1H), 7.34–7.43 (m, 4H), 7.46–7.52 (m, 2H), 7.53–7.57 (m, 1H), 7.70–7.74 (m, 1H), 7.85–7.88 (m, 1H), 7.92–7.99 (m, 2H); ¹³C NMR (125 Hz, CDCl₃) δ 42.3 (t), 63.1 (d), 83.6 (s), 122.2 (d), 123.1 (d), 123.96 (d), 124.00 (s), 125.1 (d), 127.1 (d), 128.0 (d), 128.2 (d), 129.2 (d), 129.4 (d), 129.5 (d), 131.3(d), 131.4 (s), 131.9 (s), 132.0 (d), 134.7 (s), 135.2 (d), 139.5 (s), 139.6 (s), 152.5 (s), 191.6 (s); HRMS (ESI, ion trap) calcd for C₂₅H₁₈NO₃ (M + H⁺) 380.1287, found 380.1272.

3a′,4′-Dihydro-1′H,5′H-spiro[fluorene-9,3′-oxazolo[3,4-a]quinoline]-1′,5′-dione (5f)

White solid (101 mg); R_f 0.25 (hexane–ethyl acetate, 5:1); mp 247–248 °C; IR (ATR) 1763, 1674, 1601 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 2.22 (dd, 1H, J = 3.9, 16.3 Hz), 2.62 (dd, 1H, J = 3.9, 14.8 Hz), 4.93 (dd, 1H, J = 14.8, 16.3 Hz), 7.19–7.24 (m, 1H), 7.28–7.33 (m, 1H), 7.34–7.39 (m, 1H), 7.44–7.51 (m, 2H), 7.54–7.62 (m, 2H), 7.64–7.72 (m, 3H), 7.96–8.00 (m, 1H), 8.65–8.68 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 38.4 (t), 61.2 (d), 87.8 (s), 117.3 (d), 120.6 (d), 121.1 (d), 121.3 (s), 123.8 (d), 124.5 (d), 125.2 (d), 127.8 (d), 128.2 (d), 128.6 (d), 131.0 (d), 131.2 (d), 135.8 (d), 139.8 (s), 140.1 (s), 140.3 (s), 140.6 (s), 140.8 (s), 153.4 (s), 190.5 (s); HRMS (ESI, ion trap) calcd for C₂₃H₁₆NO₃ (M + H⁺) 354.1130, found 354.1115.

(3aS,4S)-4-Methyl-3,3-diphenyl-3a,4-dihydro-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (cis-5g)

White solid (39 mg); R_f 0.4 (hexane–ethyl acetate, 5:1); mp 235–236 °C; IR (ATR) 1763, 1680, 1599 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 0.70 (d, 3H, J = 6.9 Hz), 2.92–2.97 (m, 1H), 5.32 (d, 1H, J = 2.9 Hz), 7.23–7.27 (m, 1H), 7.29–7.43 (m, 6H), 7.50–7.54 (m, 2H), 7.55–7.59 (m, 2H), 7.60–7.64 (m, 1H), 7.94–7.97 (m, 1H), 7.97–8.00 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 9.8 (q), 44.0 (d), 65.7 (d), 84.8 (s), 120.7 (d), 121.7 (s), 124.9 (d), 125.0 (d), 125.1 (d), 128.1 (d), 128.2 (d), 128.6 (d), 128.8 (d), 128.9 (d), 135.3 (d), 138.1 (s), 139.7 (s), 143.4 (s), 153.0 (s), 195.4 (s); HRMS (ESI, ion trap) calcd for C₂₄H₂₀NO₃ (M + H⁺) 370.1443, found 370.1431.

(3aS,4R)-4-Methyl-3,3-diphenyl-3a,4-dihydro-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (trans-5f)

White solid (118 mg); R_f 0.5 (hexane–ethyl acetate, 5:1); mp 207–209 °C; IR (ATR) 1748, 1676, 1601 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.11 (d, 3H, J = 6.9 Hz), 2.42–2.49 (m, 1H), 5.06 (d, 1H, J = 13.2 Hz), 7.18–7.22 (m, 3H), 7.32–7.39 (m, 3H), 7.43–7.50 (m, 3H), 7.55–7.59 (m, 2H), 7.60–7.64 (m, 1H), 7.96–8.00 (m, 1H), 8.46–8.49 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 11.7 (q), 44.1 (d), 66.4 (d), 86.7 (s), 118.4 (d), 121.1 (s), 124.1 (d), 127.3 (d), 127.8 (d), 128.0 (d), 128.3 (d), 128.6 (d), 129.1 (d), 135.5 (d), 138.5 (s), 139.7 (s), 140.4 (s), 152.8 (s), 193.9 (s); HRMS (ESI, ion trap) calcd for C₂₄H₂₀NO₃ (M + H⁺) 370.1443, found 370.1432.

6-Methoxy-1,1-diphenylfuro[3,4-c]quinolin-3(1H)-one (14a)

White solid (69 mg); R_f 0.25 (hexane–ethyl acetate, 1:1); mp 207–208 °C; IR (ATR) 1759, 1516 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 4.13 (s, 3H), 7.20 (d, 1H, J = 8.0 Hz), 7.28–7.41 (m, 11H), 7.47 (t, 1H, J = 8.0 Hz), 9.45 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 56.3 (q), 93.2 (s), 110.4 (d), 117.2 (d), 119.8 (s), 123.6 (s), 128.5 (d), 128.6 (d), 128.9 (d), 129.2 (d), 137.8 (s), 142.3 (s), 145.2 (d), 156.2 (s), 159.3 (s), 168.5 (s).; HRMS (ESI, ion trap) calcd for C₂₄H₁₈NO₃ (M + H⁺) 368.1287, found 368.1278.

6,9-Dimethoxy-1,1-diphenylfuro[3,4-c]quinolin-3(1H)-one (14b)

Yellow solid (66 mg); R_f 0.3 (hexane–ethyl acetate, 1:1); mp 296–298 °C; IR (ATR) 1753, 1607, 1597, 1530 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 3.25 (s, 3H), 4.10 (s, 3H), 6.80 (d, 1H, J = 8.8 Hz), 7.19 (d, 1H, J = 8.8 Hz), 7.23–7.35 (m, 10H), 9.46 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 54.0 (q), 56.5 (q), 96.1 (s), 107.3 (d), 111.3 (d), 117.1 (s), 120.7 (s), 127.7 (d), 128.4 (d), 128.8 (d), 138.0 (s), 142.6 (s), 146.1 (d), 148.1 (s), 150.0 (s), 158.3 (s), 168.3 (s); HRMS (ESI, ion trap) calcd for C₂₅H₂₀NO₄ (M + H⁺) 398.1392, found 392.1375.

6,8-Dimethoxy-1,1-diphenylfuro[3,4-c]quinolin-3(1H)-one (14c)

White solid (78 mg); R_f 0.35 (hexane–ethyl acetate, 1:1); mp 237–239 °C; IR (ATR) 1773, 1757, 1618, 1605, 1576, 1518, 1508 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 3.60 (s, 3H), 4.08 (s, 3H), 6.50 (s, 1H), 6.90 (s, 1H), 7.29–7.40 (m, 10H), 9.29 (s, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 55.4 (q), 56.3 (q), 92.8 (s), 95.0 (d), 103.5 (d), 120.0 (s), 124.4 (s), 128.4 (d), 128.5 (d), 129.1 (d), 137.7 (d), 139.0 (s), 142.4 (d), 157.0 (s), 157.6 (s), 159.4 (s), 168.6 (s); HRMS (ESI, ion trap) calcd for C₂₅H₂₀NO₄ (M + H⁺) 398.1392, found 392.1375.

Desilylation of 3 with 1 M HCl Aqueous (aq) and Dioxane

To a solution of 3b (230 mg, 0.5 mmol) in dioxane (5 mL) was added 1 M HCl aq (5 mL), and then the solution was stirred at 50 °C for 6 h. The mixture was neutralized with sat. NaHCO₃ aq and extracted with ethyl acetate (10 mL × 3). After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 4b (184 mg) in 95% yield.

Methyl 2-(Hydroxydiphenylmethyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (4b)

White solid (184 mg); R_f 0.5 (hexane–ethyl acetate, 2:1); mp 190–191 °C; IR (ATR) 3464 (br), 1715, 1676, 1597 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 2.10 (brs, 1H), 2.93 (d, 1H, J = 18.2 Hz), 3.07 (dd, 1H, J = 7.0, 18.2 Hz), 3.64 (s, 3H), 5.97 (brs, 1H), 7.17–7.36 (m, 10H), 7.41–7.49 (m, 3H), 7.93–7.96 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 39.1 (t), 53.4 (q), 59.5 (d), 82.8 (s), 124.5 (d), 125.3 (d), 125.8 (d), 125.9 (d), 127.1 (s), 127.3 (d), 127.5 (d), 127.8 (d), 128.6 (d), 133.5 (d), 141.6 (s), 143.7 (s), 144.0 (s), 154.8 (s), 193.2 (s); HRMS (ESI, ion trap) calcd for C₂₄H₂₂NO₄ (M + H⁺) 388.1549, found 388.1537.

Cyclization of 4b

Method 1: A solution of 4b (77 mg, 0.2 mmol) and p-TsOH (10 mg) in toluene (10 mL) was refluxed using the Dean–Stark apparatus under nitrogen atmosphere for 2 h. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 5a (60 mg, 83%). Method 2: A solution of 4b (77 mg, 0.2 mmol) and NaH (40% in oil, 12 mg, 0.2 mmol) in THF (5 mL) was stirred under nitrogen atmosphere at 25 °C for 1 h. After addition of AcOH (12 mg, 0.2 mmol), the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 5a (63 mg, 88%).

Transformation of 3h to 7a

A solution of 3h (107 mg, 0.2 mmol) and 10% Pd/C (10 mg) in HCO₂H (1 mL) and EtOH (5 mL) was stirred under nitrogen atmosphere at 50 °C for 2 h. After the solvent was removed in vacuo, the residue was dissolved in Ac₂O (2 mL) and HCO₂H (2 mL). The solution was stirred at 50 °C for 4 h under nitrogen atmosphere, and the solvent was removed in vacuo. The residue was refluxed in toluene (10 mL) in the presence of PPTS (10 mg) using the Dean–Stark apparatus under nitrogen atmosphere for 2 h. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 7a (16 mg, 25%).

2-Benzhydrylquinolin-4(1H)-one (7a)

Pale red solid (39 mg); R_f 0.25 (hexane–ethyl acetate, 1:1); mp 255–256 °C; IR (ATR) 1634, 1592 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 5.45 (s, 1H), 5.99 (s, 1H), 7.11–7.17 (m, 4H), 7.22–7.32 (m, 8H), 7.49–7.54 (m, 1H), 8.25–8.28 (m, 1H), 9.20 (brs, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 55.1 (d), 110.7 (d), 118.0 (d), 123.7 (d), 124.9 (s), 125.5 (d), 127.3 (d), 128.6 (d), 129.1 (d), 132.0 (d), 139.5 (s), 140.1 (s), 154.8 (s), 178.9 (s); HRMS (ESI, ion trap) calcd for C₂₂H₁₈NO (M + H⁺) 312.1388, found 312.1376.

2-(Bis(4-fluorophenyl)methyl)quinolin-4(1H)-one (7b)

White solid (80 mg); R_f 0.5 (hexane–ethyl acetate, 1:1); mp 255–256 °C, IR (ATR) 2808 (br), 1722, 1636, 1603, 1587, 1545, 1504 cm^–1; ¹H NMR [500 MHz, CDCl₃ + dimethyl sulfoxide (DMSO)-d₆] δ 5.48 (s, 1H), 5.84 (s, 1H), 6.98–7.03 (m, 4H), 7.10–7.15 (m, 4H), 7.27–7.31 (m, 1H), 7.44–7.47 (m, 1H), 7.52–7.56 (m, 1H), 8.25–8.27 (m, 1H), 11.18 (brs, 1H); ¹³C NMR (125 Hz, CDCl₃ + DMSO-d₆) δ 52.6 (d), 109.8 (d), 115.2 (d, J_CCF = 21.3 Hz), 117.9 (d), 122.9 (d), 124.5 (s), 124.8 (d), 130.6 (d, J_CCCF = 7.8 Hz), 131.5 (d), 135.8 (s, J_CCCCF = 2.4 Hz), 140.1 (s), 153.9 (s), 161.3 (s, J_CF = 245.6 Hz), 177.7 (s); HRMS (ESI, ion trap) calcd for C₂₂H₁₆F₂NO (M + H⁺) 348.1200, found 348.1187.

Dehydrogenation of 5 with DDQ

To a solution of 5a (71 mg, 0.2 mmol) in dioxane (5 mL) were added DDQ (57 mg, 0.25 mmol) and TMSCl (0.07 mL, 0.5 mmol), and then the solution was refluxed for 3 h. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 8a (67 mg) in 90% yield.

3,3-Diphenyl-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (8a)

White solid (67 mg); R_f 0.4 (hexane–ethyl acetate, 2:1); mp 242–244 °C; IR (ATR) 1792, 1634, 1601, 1570 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 6.36 (s, 1H), 7.39–7.45 (m, 10H), 7.54–7.58 (m, 1H), 7.78–7.82 (m, 1H), 8.36–8.39 (m, 1H), 8.94 (d, 1H, J = 8.6 Hz); ¹³C NMR (125 Hz, CDCl₃) δ 88.9 (s), 108.8 (d), 117.4 (d), 125.2 (s), 126.6 (d), 126.8 (d), 126.9 (d), 129.0 (d), 129.8 (d), 133.8 (d), 135.3 (s), 137.8 (s), 150.4 (s), 152.7 (s), 178.4 (s); HRMS (ESI, ion trap) calcd for C₂₃H₁₆NO₃ (M + H⁺) 354.1130, found 354.1122.

3,3-Bis(4-fluorophenyl)-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (8b)

White solid (69 mg); R_f 0.55 (hexane–ethyl acetate, 2:1); mp 244–246 °C; IR (ATR) 1792, 1634, 1601, 1506 cm^–1; ¹H NMR (500 MHz, CDCl₃ + DMSO-d₆) δ 6.40 (s, 1H), 7.17–7.24 (m, 4H), 7.47–7.53 (m, 4H), 7.54–7.60 (m, 1H), 7.81–7.87 (m, 1H), 8.21–8.26 (m, 1H), 8.84 (d, 1H, J = 8.6 Hz); ¹³C NMR (125 Hz, CDCl₃ + DMSO-d₆) δ 85.9 (s), 106.6 (d), 114.3 (d, J_CCF = 22.8 Hz), 115.7 (d), 123.5 (s), 124.5 (d), 125.0 (d), 127.8 (d, J_CCCF = 8.4 Hz), 131.9 (d), 132.4 (d, J_CCCCF = 2.4 Hz), 133.7 (s), 148.2 (s), 150.8 (s), 161.3 (s, J_CF = 248.9 Hz), 175.7 (s); HRMS (ESI, ion trap) calcd for C₂₃H₁₄F₂NO₃ (M + H⁺) 390.0942, found 390.0925.

1′H,5′H-Spiro[fluorene-9,3′-oxazolo[3,4-a]quinoline]-1′,5′-dione (8c)

White solid (65 mg): R_f 0.5 (hexane–ethyl acetate, 2:1); mp 252–253 °C; IR (ATR) 1788, 1643, 1636, 1630, 1603, 1572 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 5.76 (s, 1H), 7.30–7.35 (m, 4H), 7.49–7.55 (m, 2H), 7.58 (t, 1H, J = 7.6 Hz), 7.73 (d, 2H, J = 7.6 Hz), 7.83–7.88 (m, 1H), 8.36 (dd, 1H, J = 1.4, 8.0 Hz), 9.02 (d, 1H, J = 8.5 Hz); ¹³C NMR (125 Hz, CDCl₃) δ 88.5 (s), 105.9 (d), 117.2 (d), 121.0 (d), 124.6 (d), 125.6 (s), 126.8 (d), 129.1 (d), 131.7 (d), 133.6 (d), 135.4 (s), 140.81 (s), 140.84 (s), 151.5 (s), 152.1 (s), 178.3 (s); HRMS (ESI, ion trap) calcd for C₂₃H₁₄NO₄ (M + H⁺) 352.0974, found 352.0956.

Deprotection of 9 to 10

To a solution of 9a (65 mg, 0.2 mmol) in MeOH (5 mL) was added NaH (40% in oil, 12 mg, 0.2 mmol), and the solution was stirred at 25 °C for 1 h. After addition of AcOH (12 mg, 0.2 mmol), the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 9a (54 mg, 82%).

2-(Hydroxydiphenylmethyl)quinolin-4(1H)-one (9a)

White solid; R_f 0.25 (hexane–ethyl acetate, 1:2); mp 265–266 °C; IR (ATR) 2700–3000 (br), 1740, 1639, 1587, 1535 cm^–1; ¹H NMR (500 MHz, CDCl₃ + DMSO-d₆) δ 5.78 (brs, 1H), 6.80 (s, 1H), 7.27–7.39 (m, 11H), 7.55–7.60 (m, 1H), 7.68 (d, 1H, J = 8.5 Hz), 8.22 (d, 1H, J = 8.2 Hz), 10.97 (brs, 1H); ¹³C NMR (125 Hz, CDCl₃ + DMSO-d₆) δ 78.8 (s), 108.7 (d), 117.4 (d), 121.6 (d), 123.2 (s), 123.3 (d), 126.2 (d), 126.35 (d), 126.38 (d), 130.1 (d), 138.7 (s), 142.9 (s), 154.8 (s), 176.2 (s); HRMS (ESI, ion trap) calcd for C₂₂H₁₈NO₂ (M + H⁺) 328.1338, found 328.1326.

2-(Bis(4-fluorophenyl)(hydroxy)methyl)quinolin-4(1H)-one (9b)

Colorless paste (70 mg): R_f 0.45 (hexane–ethyl acetate, 1:2); IR (ATR) 3360 (br), 2818 (br), 1641, 1599, 1589, 1530, 1501 cm^–1; ¹H NMR (500 MHz, CDCl₃ + DMSO-d₆) δ 5.64 (s, 1H), 7.06–7.14 (m, 5H), 7.29 (t, 1H, J = 7.5 Hz), 7.33–7.38 (m, 4H), 7.59 (t, 1H, J = 7.5 Hz), 7.83 (d, 1H, J = 8.5 Hz), 8.09–8.12 (m, 1H), 11.23 (brs, 1H); ¹³C NMR (125 Hz, CDCl₃ + DMSO-d₆) δ 77.8 (s), 107.9 (d), 113.0 (d, J_CCF = 21.0 Hz), 117.3 (d), 121.2 (d), 123.0 (s), 123.1 (d), 128.2 (d, J_CCCF = 8.4 Hz), 130.1 (d), 138.5 (s), 138.7 (s), 154.3 (s), 160.1 (J_CF = 245.9 Hz), 175.7 (s); HRMS (ESI, ion trap) calcd for C₂₂H₁₆F₂NO₂ (M + H⁺) 364.1149, found 364.1136.

2-(9-Hydroxy-9H-fluoren-9-yl)quinolin-4(1H)-one (9c)

White solid (46 mg): R_f 0.35 (hexane–ethyl acetate, 1:2); mp 290–292 °C; IR (ATR) 3339 (br), 1620, 1599, 1572, 1553, 1514, 1506 cm^–1; ¹H NMR (500 MHz, CDCl₃ + DMSO-d₆) δ 5.30 (brs, 1H), 7.11 (brs, 1H), 7.25–7.34 (m, 3H), 7.41–7.46 (m, 2H), 7.57 (d, 2H, J = 7.6 Hz), 7.59–7.64 (m, 1H), 7.80 (d, 2H, J = 7.6 Hz), 8.02 (dd, 1H, J = 1.4, 8.0 Hz), 8.10 (d, 1H, J = 8.3 Hz), 10.46 (brs, 1H); ¹³C NMR (125 Hz, CDCl₃ + DMSO-d₆) δ 80.3 (s), 104.2 (d), 117.9 (d), 119.0 (d), 122.1 (d), 123.6 (d), 123.7 (d), 124.1 (s), 127.2 (d), 128.3 (d), 130.3 (d), 138.6 (s), 139.1 (s), 147.1 (s), 153.7 (s), 176.9 (s); HRMS (ESI, ion trap) calcd for C₂₂H₁₆NO₂ (M + H⁺) 326.1181, found 326.1168.

Electroreduction of 1f–h

The electroreduction of 1f (1 mmol) was carried out under the same conditions as described above. The crude product was dissolved in EtOH (5 mL), and to the solution was added TMSCl (0.64 mL, 5 mmol). After the solution was stirred at 25 °C for 1 h, the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 10a (298 mg) in 63% yield.

Diethyl 4-Hydroxy-2-(hydroxydiphenylmethyl)quinoline-1,3(2H)-dicarboxylate (10a)

White solid (298 mg); R_f 0.5 (hexane–ethyl acetate, 5:1); mp 183–185 °C; IR (ATR) 3450 (br), 1697, 1638, 1609, 1593, 1558 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.04 (t, 3H, J = 7.2 Hz), 1.20–1.28 (m, 3H), 1.71 (brs, 1H), 3.38–3.46 (m, 1H), 3.91–3.98 (m, 1H), 4.05–4.14 (m, 1H), 4.21–4.28 (m, 1H), 6.50 (s, 1H), 7.07–7.35 (m, 10H), 7.39–7.44 (m, 2H), 7.61–7.67 (m, 2H), 7.79–7.84 (m, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 13.8 (q), 14.3 (q), 56.4 (d), 60.8 (t), 62.6 (t), 83.4 (s), 95.5 (s), 124.2 (d), 124.8 (d), 125.0 (s), 125.4 (d), 126.7 (d), 127.0 (d), 127.1 (d), 127.2 (d), 127.4 (d), 127.7 (d), 130.8 (d), 138.4 (s), 142.7 (s), 143.5 (s), 154.2 (s), 164.5 (s), 170.8 (s); HRMS (ESI, ion trap) calcd for C₂₈H₂₈NO₆ (M + H⁺) 474.1917, found 474.1898.

Diethyl 2-(Bis(4-fluorophenyl)(hydroxy)methyl)-4-hydroxyquinoline-1,3(2H)-dicarboxylate (10b)

White solid (280 mg); R_f 0.4 (hexane–ethyl acetate, 5:1); mp 191–193 °C; IR (ATR) 3443 (br), 1697, 1634, 1607, 1558, 1506 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.08 (t, 3H, J = 7.2 Hz), 1.24 (t, 3H, J = 7.0 Hz), 1.75 (brs, 1H), 3.53–3.61 (m, 1H), 3.96–4.04 (m, 1H), 4.07–4.15 (m, 1H), 4.22–4.30 (m, 1H), 6.43 (s, 1H), 6.88–6.94 (m, 2H), 6.96–7.01 (m, 2H), 7.05–7.14 (m, 1H), 7.19–7.23 (m, 1H), 7.30–7.39 (m, 3H), 7.55–7.61 (m, 2H), 7.79 (dd, 1H, J = 1.7, 7.9 Hz), 12.54 (brs, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 13.8 (q), 14.3 (q), 56.4 (d), 61.0 (t), 62.8 (t), 82.7 (s), 95.2 (s), 114.2 (d, J_CCF = 21.6 Hz), 114.5 (d, J_CCF = 21.6 Hz), 124.4 (d), 124.8 (s), 124.9 (d), 125.4 (d), 128.5 (d, J_CCCF = 7.5 Hz), 128.9 (d, J_CCCF = 7.2 Hz), 131.0 (s), 138.1 (s), 138.5 (s), 139.2 (s), 161.9 (s, J_CF = 247.1 Hz), 162.0 (s, J_CF = 245.9 Hz), 164.7 (s), 170.6 (s); HRMS (ESI, ion trap) calcd for C₂₈H₂₆F₂NO₆ (M + H⁺) 510.1728, found 510.1714.

Diethyl 4-Hydroxy-2-(hydroxydiphenylmethyl)-6-methoxyquinoline-1,3(2H)-dicarboxylate (10c)

White solid (307 mg); R_f 0.2 (hexane–ethyl acetate, 5:1); mp 160–161 °C; IR (ATR) 3468 (br), 1697, 1638, 1612, 1570, 1560 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.02 (t, 3H, J = 7.1 Hz), 1.18–1.30 (m, 3H), 1.67 (brs, 1H), 3.33–3.44 (m, 1H), 3.85 (s, 3H), 3.87–3.98 (m, 1H), 4.02–4.16 (m, 1H), 4.20–4.28 (m, 1H), 6.45 (brs, 1H), 6.83–7.06 (m, 2H), 7.13–7.44 (m, 9H), 7.62–7.70 (m, 2H), 12.57 (brs, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 13.7 (q), 14.3 (q), 55.5 (q), 56.3 (d), 60.8 (t), 62.5 (t), 83.3 (s), 107.7 (d), 117.8 (d), 125.9 (s), 126.6 (d), 126.96 (d), 127.03 (d), 127.2 (d), 127.4 (d), 127.8 (d), 131.8 (s), 142.7 (s), 143.7 (s), 154.5 (s), 156.6 (s), 164.3 (s), 170.8 (s); HRMS (ESI, ion trap) calcd for C₂₉H₃₀NO₇ (M + H⁺) 504.2022, found 504.2014.

Diethyl 2-(Bis(4-fluorophenyl)(hydroxy)methyl)-4-hydroxy-6-methoxyquinoline-1,3(2H)-dicarboxylate (10d)

White solid (351 mg); R_f 0.45 (hexane–ethyl acetate, 5:1); mp 180–181 °C; IR (ATR) 3441 (br), 1705, 1636, 1612, 1599, 1570, 1506 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.06 (t, 3H, J = 7.0 Hz), 1.17–1.28 (m, 3H), 1.71 (brs, 1H), 3.49–3.58 (m, 1H), 3.85 (s, 3H), 3.94–4.03 (m, 1H), 4.05–4.15 (m, 1H), 4.21–4.29 (m, 1H), 6.38 (brs, 1H), 6.85–7.03 (m, 6H), 7.29 (d, 1H, J = 2.9 Hz), 7.32–7.38 (m, 2H), 7.57–7.63 (m, 2H), 12.59 (brs, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 13.8 (q), 14.3 (q), 55.6 (q), 56.2 (d), 61.0 (t), 62.7 (t), 82.7 (s), 107.8 (d), 114.2 (d, J_CCF = 20.4 Hz), 114.6 (d, J_CCF = 20.4 Hz), 118.0 (d), 125.7 (s), 126.7 (d), 128.5 (d, J_CCCF = 7.8 Hz), 128.8 (d, J_CCCF = 7.8 Hz), 138.5 (s), 139.4 (s), 154.5 (s), 156.8 (s), 161.8 (s, J_CF = 246.2 Hz), 162.0 (s, J_CF = 246.2 Hz), 164.5 (s), 170.7 (s); HRMS (ESI, ion trap) calcd for C₂₉H₂₈F₂NO₇ (M + H⁺) 540.1834, found 540.1827.

Diethyl 4-Hydroxy-2-(hydroxydiphenylmethyl)-7-methoxyquinoline-1,3(2H)-dicarboxylate (10e)

White solid (307 mg); R_f 0.45 (hexane–ethyl acetate, 2:1); mp 150–152 °C; IR (ATR) 3462 (br), 1749, 1721, 1697, 1636, 1609, 1558, 1504 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.04 (t, 3H, J = 7.2 Hz), 1.25 (t, 3H, J = 7.2 Hz), 1.87 (brs, 1H), 3.39–3.47 (m, 1H), 3.77 (s, 3H), 3.90–3.98 (m, 1H), 4.05–4.12 (m, 1H), 4.20–4.27 (m, 1H), 6.50 (brs, 1H), 6.68 (brs, 1H), 6.74 (dd, 1H, J = 2.6, 8.6 Hz), 7.14–7.18 (m, 1H), 7.20–7.28 (m, 3H), 7.29–7.34 (m, 2H), 7.43–7.47 (m, 2H), 7.62–7.66 (m, 2H), 7.72 (d, 1H, J = 8.6 Hz), 12.57 (brs, 1H); ¹³C NMR (125 Hz, CDCl₃) δ 13.8 (q), 14.3 (q), 55.4 (q), 56.7 (d), 60.6 (t), 62.6 (t), 83.4 (s), 110.7 (d), 111.1 (s), 117.9 (s), 125.6 (d), 126.7 (d), 127.01 (d), 127.04 (d), 127.2 (d), 127.4 (d), 127.6 (d), 140.2 (s), 142.8 (s), 143.4 (s), 154.1 (s), 161.8 (s), 165.0 (s), 170.8 (s); HRMS (ESI, ion trap) calcd for C₂₉H₃₀NO₇ (M + H⁺) 504.2022, found 504.2000.

Cyclization of 10a and 10b

A solution of 10a (237 mg, 0.5 mmol) and NaH (40% in oil, 30 mg, 0.5 mmol) in THF (10 mL) was stirred under nitrogen atmosphere at 25 °C for 1 h. After addition of AcOH (30 mg, 0.5 mmol), the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 11a (190 mg, 89%).

Ethyl (3aS,4R)-1,5-Dioxo-3,3-diphenyl-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-4-carboxylate (11a)

White solid (190 mg); R_f 0.3 (hexane–ethyl acetate, 5:1); mp 210–211 °C; IR (ATR) 1769, 1721, 1692, 1680, 1601 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.09 (t, 3H, J = 7.5 Hz), 3.60–3.67 (m, 1H), 3.64 (d, 1H, J = 13.4 Hz), 4.00–4.07 (m, 1H), 5.73 (d, 1H, J = 13.4 Hz), 7.21–7.26 (m, 3H), 7.31–7.36 (m, 3H), 7.41–7.45 (m, 1H), 7.46–7.52 (m, 2H), 7.62–7.67 (m, 1H), 7.83–7.88 (m, 2H), 7.96 (dd, 1H, J = 1.7, 8.0 Hz), 8.07 (d, 1H, J = 8.4 Hz); ¹³C NMR (125 Hz, CDCl₃) δ 13.6 (q), 57.1 (d), 61.7 (t), 64.5 (d), 86.0 (s), 120.4 (d), 121.8 (s), 124.9 (d), 126.8 (d), 127.8 (d), 127.9 (d), 128.3 (d), 128.7 (d), 128.9 (d), 129.0 (d), 136.1 (d), 137.2 (s), 139.3 (s), 140.9 (s), 152.3 (s), 167.4 (s), 187.7 (s); HRMS (ESI, ion trap) calcd for C₂₆H₂₂NO₅ (M + H⁺) 428.1498, found 428.1481.

Ethyl 3,3-Bis(4-fluorophenyl)-1,5-dioxo-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinoline-4-carboxylate (11b)

White solid (202 mg); R_f 0.4 (hexane–ethyl acetate, 5:1); mp 183–185 °C; IR (ATR) 1755, 1722, 1695, 1680, 1599, 1508 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.13 (t, 3H, J = 7.0 Hz), 3.60 (d, 1H, J = 13.8 Hz), 3.67–3.74 (m, 1H), 4.03–4.11 (m, 1H), 5.65 (d, 1H, J = 13.8 Hz), 7.00–7.06 (m, 2H), 7.15–7.22 (m, 4H), 7.24–7.28 (m, 1H), 7.64–7.69 (m, 1H), 7.81–7.86 (m, 2H), 7.97 (dd, 1H, J = 1.7, 8.0 Hz), 8.07 (d, 1H, J = 8.5 Hz); ¹³C NMR (125 Hz, CDCl₃) δ 13.6 (q), 57.0 (d), 62.0 (t), 64.6 (d), 85.2 (s), 115.4 (d, J_CCF = 22.2 Hz), 115.8 (d, J_CCF = 21.6 Hz), 120.4 (d), 121.7 (s), 125.0 (d), 127.9 (d), 128.8 (d, J_CCCF = 8.4 Hz), 130.0 (d, J_CCCF = 8.4 Hz), 133.1 (s, J_CCCCF = 2.4 Hz), 136.2 (s), 136.6 (s, J_CCCCF = 2.4 Hz), 139.1 (s), 151.9 (s), 162.9 (s, J_CF = 250.1 Hz), 167.5 (s), 187.3 (s); HRMS (ESI, ion trap) calcd for C₂₆H₂₀F₂NO₅ (M + H⁺) 464.1310, found 464.1301.

Dehydrogenation of 11a and 11b with DDQ

To a solution of 11a (85 mg, 0.2 mmol) in dioxane (5 mL) were added DDQ (57 mg, 0.25 mmol) and TMSCl (0.07 mL, 0.5 mmol), and then the solution was refluxed for 48 h. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 12a (23 mg, 25%).

Ethyl 1,5-Dioxo-3,3-diphenyl-3,5-dihydro-1H-oxazolo[3,4-a]quinoline-4-carboxylate (12a)

White solid (23 mg); R_f 0.2 (hexane–ethyl acetate, 5:1); mp 184–186 °C; IR (ATR) 1790, 1726, 1634, 1601, 1572 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 0.95 (t, 3H, J = 6.9 Hz), 3.77 (q, 2H, J = 6.9 Hz), 7.40–7.48 (m, 10H), 7.56–7.60 (m, 1H), 7.80–7.84 (m, 1H), 8.40 (dd, 1H, J = 1.6, 8.0 Hz), 8.94 (d, 1H, J = 8.6 Hz); ¹³C NMR (125 Hz, CDCl₃) δ 13.5 (q), 61.8 (t), 90.6 (s), 116.7 (s), 117.6 (d), 124.9 (s), 127.0 (d), 127.1 (d), 128.4 (d), 128.9 (d), 130.0 (d), 134.2 (d), 135.1 (s), 135.6 (s), 150.2 (s), 163.0 (s), 175.5 (s); HRMS (ESI, ion trap) calcd for C₂₆H₂₀NO₅ (M + H⁺) 426.1341, found 426.1329.

Ethyl 3,3-Bis(4-fluorophenyl)-1,5-dioxo-3,5-dihydro-1H-oxazolo[3,4-a]quinoline-4-carboxylate (12b)

Colorless paste; R_f 0.35 (hexane–ethyl acetate, 5:1); IR (ATR) 1802, 1771, 1724, 1690, 1638, 1601, 1508 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.01 (t, 3H, J = 7.0 Hz), 3.83 (q, 2H, J = 7.0 Hz), 7.09–7.14 (m, 4H), 7.39–7.44 (m, 4H), 7.57–7.61 (m, 1H), 7.82–7.86 (m, 1H), 8.38–8.42 (m, 1H), 8.92 (d, 1H, J = 8.7 Hz); ¹³C NMR (125 Hz, CDCl₃) δ 19.5 (q), 62.0 (t), 89.5 (s), 115.6 (d, J_CCF = 22.2 Hz), 116.5 (s), 117.6 (d), 124.8 (s), 127.0 (d), 127.3 (d), 131.1 (d, J_CCCF = 8.4 Hz), 131.4 (s, J_CCCCF = 3.6 Hz), 134.4 (d), 135.0 (s), 149.8 (s), 149.9 (s), 163.1 (s), 163.5 (s, J_CF = 250.07 Hz), 175.4 (s); HRMS (ESI, ion trap) calcd for C₂₆H₁₈F₂NO₅ (M + H⁺) 462.1153, found 462.1153.

Electroreduction of 1l–n

The electroreduction of 1m (1 mmol) was carried out under the same conditions as described above. The crude product was dissolved in CH₂Cl₂ (10 mL), and to the solution was added TFA (0.64 mL, 1 mmol). After the solution was stirred under nitrogen atmosphere at 25 °C for 12 h, the solvent was removed in vacuo. To the mixture was added sat. NaHCO₃ aq (10 mL) and extracted with ethyl acetate (10 mL × 3). After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 15b (210 mg) in 48% yield.

4-Ethyl-5,6,7-trifluoro-3,3-diphenyl-3a,9a-dihydrofuro[3,4-b]quinoline-1,9(3H,4H)-dione (15b)

White solid (184 mg); R_f 0.6 (hexane–ethyl acetate, 2:1); mp 213–214 °C; IR (ATR) 1780, 1678, 1634, 1512 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.11 (t, 3H, J = 7.0 Hz), 3.43–3.53 (m, 1H), 3.83–3.92 (m, 1H), 3.93 (d, 1H, J = 9.2 Hz), 4.91 (d, 1H, J = 9.2 Hz), 6.99–7.06 (m, 3H), 7.14–7.23 (m, 3H), 7.36–7.41 (m, 1H), 7.41–7.47 (m, 2H), 7.62–7.67 (m, 2H); ¹³C NMR (125 Hz, CDCl₃) δ 13.3 (q), 50.0 (d), 51.9 (t), 67.4 (d), 90.6 (s), 109.5 (d, J_CCF = 18.6 Hz, J_CCCF = 2.4 Hz), 120.4 (s), 126.0 (d), 126.6 (d), 127.7 (d), 128.4 (d), 128.71 (d), 128.74 (d), 136.7 (s, J_CCF = 7.2 Hz), 137.4 (s), 142.8 (s, J_CF = 250.7 Hz, J_CCF = 15.6 Hz), 144.8 (s, J_CF = 259.1 Hz, J_CCF = 15.6 Hz), 145.5 (s, J_CF = 248.3 Hz, J_CCF = 10.8 Hz, J_CCCF = 2.4 Hz), 167.9 (s), 180.9 (s); HRMS (ESI, ion trap) calcd for C₂₅H₁₉F₃NO₃ (M + H⁺) 438.1317, found 438.1301.

4-Ethyl-5,6,7-trifluoro-3,3-bis(4-fluorophenyl)-3a,9a-dihydrofuro[3,4-b]quinoline-1,9(3H,4H)-dione (15c)

Yellow solid (142 mg); R_f 0.5 (hexane–ethyl acetate, 2:1); mp 203–205 °C; IR (ATR) 1788, 1672, 1634, 1605, 1506 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 1.13 (t, 3H, J = 7.0 Hz), 3.41–3.50 (m, 1H), 3.85–3.93 (m, 1H), 3.96 (d, 1H, J = 9.2 Hz), 4.89 (d, 1H, J = 9.2 Hz), 6.71–6.77 (m, 2H), 7.10–7.19 (m, 4H), 7.20–7.25 (m, 1H), 7.57–7.63 (m, 2H); ¹³C NMR (125 Hz, CDCl₃) δ 13.3 (q), 49.7 (d), 52.0 (t), 52.1 (t), 67.3 (d), 89.8 (s), 109.6 (d, J_CCF = 18.6 Hz, J_CCCF = 2.4 Hz), 114.7 (d, J_CCF = 21.9 Hz), 115.8 (d, J_CCF = 21.6 Hz), 120.1 (s), 128.0 (d, J_CCCF = 8.4 Hz), 128.5 (d, J_CCCF = 8.4 Hz), 133.2 (s, J_CCCCF = 3.6 Hz), 136.6 (s, J_CCF = 7.2 Hz), 137.5 (s, J_CCCCF = 3.6 Hz), 142.8 (s, J_CF = 251.9 Hz, J_CCF = 13.8 Hz), 145.0 (s, J_CF = 260.9 Hz, J_CCF = 14.4 Hz), 145.6 (s, J_CF = 249.8 Hz, J_CCF = 11.1 Hz), 162.5 (s, J_CF = 249.8 Hz), 162.6 (s, J_CF = 249.5 Hz), 167.6 (s), 180.6 (s); HRMS (ESI, ion trap) calcd for C₂₅H₁₇F₅NO₃ (M + H⁺) 474.1129, found 474.1117.

6-Chloro-4-cyclopropyl-7-fluoro-3,3-diphenyl-3a,9a-dihydrofuro[3,4-b]quinoline-1,9(3H,4H)-dione (15d)

Yellow solid (228 mg); R_f 0.4 (hexane–ethyl acetate, 2:1); mp 209–210 °C; IR (ATR) 1775, 1665, 1655, 1612, 1564 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 0.64–0.71 (m, 1H), 1.02–1.12 (m, 2H), 1.14–1.20 (m, 1H), 2.65–2.70 (m, 1H), 3.90 (d, 1H, J = 9.7 Hz), 5.38 (d, 1H, J = 9.7 Hz), 6.83 (d, 1H, J = 5.7 Hz), 7.00–7.11 (m, 5H), 7.18 (d, 1H, J = 8.9 Hz), 7.37–7.44 (m, 3H), 7.63–7.69 (m, 2H); ¹³C NMR (125 Hz, CDCl₃) δ 10.7 (t), 12.4 (t), 32.5 (d), 50.7 (d), 64.7 (d), 91.4 (s), 113.7 (d, J_CCF = 22.8 Hz), 116.7 (d), 118.3 (d, J_CCCF = 5.4 Hz), 127.5 (d), 127.7 (d), 127.8 (d), 128.5 (d), 128.7 (d), 129.3 (d), 129.3 (s), 137.3 (s), 140.2 (s), 146.5 (s), 150.3 (s, J_CF = 242.3 Hz), 167.9 (s), 180.6 (s); HRMS (ESI, ion trap) calcd for C₂₆H₂₀ClFNO₃ (M + H⁺) 448.1116, found 448.1112.

Dehydrogenation of 15 with DDQ

To a solution of 15b (87 mg, 0.2 mmol) in dioxane (5 mL) were added DDQ (57 mg, 0.25 mmol) and TMSCl (0.07 mL, 0.5 mmol), and then the solution was stirred at 25 °C for 1 h. After the insoluble solid was filtered off, to the filtrate was added sat. NaHCO₃ aq (10 mL) and extracted with ethyl acetate (10 mL × 3). After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel (hexane–EtOAc) to give 16b (83 mg) in 95% yield.

4-Ethyl-5,6,7-trifluoro-3,3-diphenylfuro[3,4-b]quinoline-1,9(3H,4H)-dione (16b)

White solid (83 mg); R_f 0.25 (hexane–ethyl acetate, 2:1); mp 175–176 °C; IR (ATR) 1768, 1692, 1655, 1628, 1605, 1570 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 0.37–0.42 (m, 3H), 4.17–4.40 (m, 2H), 7.36–7.52 (m, 10H), 8.27–8.32 (m, 1H); ¹³C NMR (125 Hz, CDCl₃ + DMSO-d₆) δ 12.4 (q), 12.5 (q), 47.8 (t), 48.0 (t), 87.7 (s), 100.6 (s), 103.8 (s), 108.5 (d, J_CCF = 18.3 Hz, J_CCCF = 3.0 Hz), 112.5 (s), 127.7 (d), 128.2 (d), 128.5 (s), 129.1 (d), 150.2 (s), 164.0 (s), 166.9 (s); HRMS (ESI, ion trap) calcd for C₂₅H₁₇F₃NO₃ (M + H⁺) 436.1161, found 436.1141.

4-Ethyl-5,6,7-trifluoro-3,3-bis(4-fluorophenyl)furo[3,4-b]quinoline-1,9(3H,4H)-dione (16c)

Yellow solid (68 mg); R_f 0.4 (ethyl acetate, 2:1); mp 289–290 °C; IR (ATR) 1778, 1651, 1634, 1628, 1603, 1566, 1558, 1506 cm^–1; ¹H NMR (500 MHz, CDCl₃ + DMSO-d₆) δ 0.48–0.53 (m, 3H), 4.21–4.34 (m, 2H), 7.18–7.25 (m, 4H), 7.41–7.49 (m, 4H), 8.14–8.20 (m, 1H); ¹³C NMR (125 Hz, CDCl₃ + DMSO-d₆) δ 12.5 (q), 12.6 (q), 47.5 (t), 47.6 (t), 86.4 (s), 100.7 (s), 103.7 (s), 108.3 (d, J_CCF = 18.9 Hz, J_CCCF = 3.6 Hz), 112.3 (s), 115.3 (d, J_CCF = 22.2 Hz), 125.2 (brs), 126.1 (brs), 128.4 (s), 129.9 (d, J_CCCF = 8.4 Hz), 130.5 (brs), 150.0 (s), 162.1 (s, J_CF = 251.0 Hz), 163.3 (s), 166.3 (s); HRMS (ESI, ion trap) calcd for C₂₅H₁₅F₅NO₃ (M + H⁺) 472.0972, found 472.0964.

6-Chloro-4-cyclopropyl-7-fluoro-3,3-diphenylfuro[3,4-b]quinoline-1,9(3H,4H)-dione (16d)

Yellow paste (65 mg); R_f 0.55 (hexane–ethyl acetate, 1:1); mp 282–283 °C; IR (ATR) 1771, 1645, 1609, 1585, 1543 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ 0.61–0.66 (m, 2H), 0.77–0.83 (m, 2H), 2.77–2.82 (m, 1H), 7.39–7.47 (m, 10H), 8.08 (d, 1H, J = 5.9 Hz), 8.23 (d, 1H, J = 8.6 Hz); ¹³C NMR (125 Hz, CDCl₃) δ 12.7 (t), 31.6 (d), 89.1 (s), 107.2 (s), 113.6 (d, J_CCF = 22.8 Hz), 121.6 (d), 127.0 (s, J_CF = 19.8 Hz), 128.8 (d), 129.0 (d), 129.6 (s, J_CCCF = 5.7 Hz), 129.8 (d), 136.5 (s), 139.4 (s), 155.9 (s, J_CF = 251.9 Hz), 165.0 (s), 169.5 (s), 171.7 (s); HRMS (ESI, ion trap) calcd for C₂₉H₁₈ClFNO₃ (M + H⁺) 446.0959, found 446.0945.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b03342.

¹H and ¹³C NMR spectra of compounds; X-ray crystallography data (ortep) of 3a, 3h, cis-3k, 5a, cis-5g, trans-5g, 7b, 8a, 9a, 10a, 11a, 12a, 14a, 15b, and 16b; CV data of 1a–n; and DFT calculation data of 1f–k (PDF)
X-ray crystallography (crystallographic information file) data for 3a, 3h, cis-3k, 5a, cis-5g, trans-5g, 7b, 8a, 9a, 10a, 11a, 12a, 14a, 15b, and 16b (ZIP)

The authors declare no competing financial interest.

Supplementary Material

ao9b03342_si_001.pdf^{(6.3MB, pdf)}

ao9b03342_si_002.zip^{(60.4KB, zip)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao9b03342_si_001.pdf^{(6.3MB, pdf)}

ao9b03342_si_002.zip^{(60.4KB, zip)}

[ref1] a Nilsen A.; Miley G. P.; Forquer I. P.; Mather M. W.; Katneni K.; Li Y. X.; Pou S.; Pershing A. M.; Stickles A. M.; Ryan E.; Kelly J. X.; Doggett J. S.; White K. L.; Hinrichs D. J.; Winter R. W.; Charman S. A.; Zakharov L. N.; Bathurst I.; Burrows J. N.; Vaidya A. B.; Riscoe M. K. Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers. J. Med. Chem. 2014, 57, 3818–3834. 10.1021/jm500147k. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Cui S.-F.; Addla D.; Zhou C.-H. Novel 3-Aminothiazolquinolones: Design, Synthesis, Bioactive Evaluation, SARs, and Preliminary Antibacterial Mechanism. J. Med. Chem. 2016, 59, 4488–4510. 10.1021/acs.jmedchem.5b01678. [DOI] [PubMed] [Google Scholar]; c Miliutina M.; Ejaz S. A.; Khan A. U.; Iaroshenko V. O.; Villinger A.; Iqbal J.; Langer P. Synthesis, alkaline phosphatase inhibition studies and molecular docking of novel derivatives of 4-quinolones. Eur. J. Med. Chem. 2017, 126, 408–420. 10.1016/j.ejmech.2016.11.036. [DOI] [PubMed] [Google Scholar]; d Zhang Z.; Xiao X.; Su T.; Wu J.; Ren J.; Zhu J.; Zhang X.; Cao R.; Du R. Synthesis, structure-activity relationships and preliminary mechanism of action of novel water-soluble 4-quinolone-3-carboxamides as antiproliferative agents. Eur. J. Med. Chem. 2017, 140, 239–251. 10.1016/j.ejmech.2017.09.017. [DOI] [PubMed] [Google Scholar]; e Insuasty D.; Robledo S. M.; Véelez I. D.; Cuervo P.; Insuasty B.; Quiroga J.; Nogueras M.; Cobo J.; Abonia R. A Schmidt rearrangement-mediated synthesis of novel tetrahydrobenzo[1,4]diazepin-5-ones as potential anticancer and antiprotozoal agents. Eur. J. Med. Chem. 2017, 141, 567–583. 10.1016/j.ejmech.2017.10.024. [DOI] [PubMed] [Google Scholar]

[ref2] a Bisachi G. S. Origins of the Quinolone Class of Antibacterials: An Expanded “Discovery Story”. J. Med Chem. 2015, 58, 4874–4882. 10.1021/jm501881c. [DOI] [PubMed] [Google Scholar]; b Fan Y.-L.; Cheng X.-W.; Wu J.-B.; Liu M.; Zhang F.-Z.; Xu Z.; Feng L.-S. Antiplasmodial and antimalarial activities of quinolone derivatives: An overview. Eur. J. Med. Chem. 2018, 146, 1–14. 10.1016/j.ejmech.2018.01.039. [DOI] [PubMed] [Google Scholar]; c Zhang G.-F.; Zhang S.; Pan B.; Liu X.; Feng L.-S. 4-Quinolone derivatives and their activities against Gram positive pathogens. Eur. J. Med. Chem. 2018, 143, 710–723. 10.1016/j.ejmech.2017.11.082. [DOI] [PubMed] [Google Scholar]

[ref3] a Boteva A. A.; Krasnykh O. P. The Methods of Synthesis, Modification, and Biological Activity of 4-Quinolones. Chem. Heterocycl. Compd. 2009, 45, 757–785. 10.1007/s10593-009-0360-1. [DOI] [Google Scholar]; b Naeem A.; Badshah S. L.; Muska M.; Ahmad N.; Khan K. The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity. Molecules 2016, 21, 268–286. 10.3390/molecules21040268. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Sajadikhah S. S.; Lotfifar N. Recent methods of 4-quinolone synthesis. Chem. Heterocycl. Compd. 2018, 54, 587–589. 10.1007/s10593-018-2311-1. [DOI] [Google Scholar]

[ref4] a Kise N.; Sakurai T. Electroreductive intramolecular coupling of N-(oxoalkyl)phthalimides: complementary method to samarium(II) iodide reduction. Tetrahedron Lett. 2010, 51, 70–74. 10.1016/j.tetlet.2009.10.076. [DOI] [Google Scholar]; b Kise N.; Isemoto S.; Sakurai T. Electroreductive Intramolecular Coupling of Phthalimides with Aromatic Aldehydes: Application to the Synthesis of Lennoxamine. J. Org. Chem. 2011, 76, 9856–9860. 10.1021/jo2018735. [DOI] [PubMed] [Google Scholar]; c Kise N.; Isemoto S.; Sakurai T. Electroreductive intermolecular coupling of phthalimides with aldehydes: application to the synthesis of alkylideneisoindolin-1-ones. Tetrahedron 2012, 68, 8805–8816. 10.1016/j.tet.2012.07.094. [DOI] [Google Scholar]

[ref5] Kise N.; Sueyoshi A.; Takeuchi S.; Sakurai T. Electroreductive Intermolecular Coupling of 3-Methoxycarbonylindoles with Ketones. Org. Lett. 2013, 15, 2746–2749. 10.1021/ol4010799. [DOI] [PubMed] [Google Scholar]

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[ref10] Bichovski P.; Haas T. M.; Kratzert D.; Streuff J. Synthesis of Bridged Benzazocines and Benzoxocines by a Titanium-Catalyzed Double-Reductive Umpolung Strategy. Chem. Eur. J. 2015, 21, 2339–2342. 10.1002/chem.201405852. [DOI] [PubMed] [Google Scholar]

[ref11] Alvarez M.; Ajana W.; López-Calahorra F.; Joule J. A. Synthesis of Benz[b]acridine-6,11,12-triones. J. Chem. Soc., Perkin Trans. 1 1994, 917–919. 10.1039/P19940000917. [DOI] [Google Scholar]

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run	3	5	% yield^a
1	3b	5a	89
2	3c	5b	87
3	3d	5c	75
4	3e	5d	88
5	3f	5e	83
6	3g	5f	92
7	3h	5a	85
8	3i	5b	81
9	3j	5a	84

run	3	5	% yield^a
1	3b	5a	89
2	3c	5b	87
3	3d	5c	75
4	3e	5d	88
5	3f	5e	83
6	3g	5f	92
7	3h	5a	85
8	3i	5b	81
9	3j	5a	84

PERMALINK

Electroreductive Intermolecular Coupling of 4-Quinolones with Benzophenones: Synthesis of 2-Substituted 4-Quinolones

Naoki Kise

Yoshie Yoshimura

Tatsuhiro Manto

Toshihiko Sakurai

Abstract

Introduction

Figure 1.

Scheme 1. Electroreductive Coupling of 1-Alkoxycarbonyl-4-quinolones with Benzophenones.

Scheme 2. Electroreductive Coupling of 1,3-Diethoxycarbonyl-4-quinolones with Benzophenones.

Scheme 3. Electroreductive Coupling of Polyhalogenated 3-Alkoxycarbonyl-4-quinolones with Benzophenones.

Results and Discussion

Electroreductive Coupling of 1-Alkoxycarbonyl-4-quinolones with Benzophenones

Scheme 4. Electroreductive Coupling of 1-Methyl-4-quinolone with Benzophenone.

Table 1. Electroreductive Coupling of 1-Alkoxycarbonyl-4-quinolones 1b–d with 2a–fa.

Table 2. Desilylation of 3b–j with TBAF.

Scheme 5. Electroreductive Coupling of 1e with 2a.

Scheme 6. Desilylation of 3b with 1 M HCl and Subsequent Cyclization to 5b.

Scheme 7. Transformation of 3h and 3i to 7a and 7b.

Table 3. Dehydrogenation and Subsequent Deprotection of 5a, 5b, and 5f.

Electroreductive Coupling of 1,3-Diethoxycarbonyl-4-quinolones with Benzophenones

Table 4. Electroreductive Coupling of 1,3-Diethoxycarbonyl-4-quinolones 1f–h with 2a and 2b.

Scheme 8. Cyclization and Subsequent Dehydrogenation of 11a and 11b.

Table 5. Electroreductive Coupling of 1,3-Diethoxycarbonyl-4-quinolones 1i–k with 2a.

Table 6. Desilylation of 13a–c with TBAF.

Electroreductive Coupling of 3-Alkoxycarbonyl-1-alkyl-4-quinolones with Benzophenones

Table 7. Electroreductive Coupling of 3-Alkoxycarbonyl-4-quinolones 1l–n with 2a and 2b.

Table 8. Dehydrogenation of 15b–d.

Reaction Mechanism of the Electroreductive Coupling 4-Quinolones with Benzophenones

Table 9. Ep values of 1a–n and 2a–f Derived from CV at 25 °C.

Scheme 9. Presumed Reaction Mechanism of Electroreductive Coupling of 4-Quinolones 1 with Benzophenones 2.

Scheme 10. Presumed Reaction Mechanism of Electroreductive Coupling of 8-Methoxy-4-quinolones 1i–k with Benzophenone 2a.

Table 10. Absolute Values of the LUMO Coefficients and Mulliken Charges at the 2 and 4 C Carbons of 1f–k Calculated at the B3LYP/6-311+G(2d,p) Level.

Conclusions

Experimental Section

General Methods

Starting Materials

Methyl 3-Methyl-4-oxoquinoline-1(4H)-carboxylate (1e)

Diethyl 6-Methoxy-4-oxoquinoline-1,3(4H)-dicarboxylate (1g)

Diethyl 7-Methoxy-4-oxoquinoline-1,3(4H)-dicarboxylate (1h)

Diethyl 8-Methoxy-4-oxoquinoline-1,3(4H)-dicarboxylate (1i)

Diethyl 5,8-Dimethoxy-4-oxoquinoline-1,3(4H)-dicarboxylate (1j)

Diethyl 6,8-Dimethoxy-4-oxoquinoline-1,3(4H)-dicarboxylate (1k)

Typical Procedure of Electroreductive Coupling

2-(Diphenyl((trimethylsilyl)oxy)methyl)-1-methyl-2,3-dihydroquinolin-4(1H)-one (3a)

Methyl 2-(Diphenyl((trimethylsilyl)oxy)methyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3b)

Methyl 2-(Bis(4-fluorophenyl)((trimethylsilyl)oxy)methyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3c)

Methyl 4-Oxo-2-(9-((trimethylsilyl)oxy)-9H-xanthen-9-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (3d)

Methyl 4-Oxo-2-(5-((trimethylsilyl)oxy)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (3e)

Methyl 4-Oxo-2-(5-((trimethylsilyl)oxy)-5H-dibenzo[a,d][7]annulen-5-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (3f)

Methyl 4-Oxo-2-(9-((trimethylsilyl)oxy)-9H-fluoren-9-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (3g)

Benzyl 2-(Diphenyl((trimethylsilyl)oxy)methyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3h)

Benzyl 2-(Bis(4-fluorophenyl)((trimethylsilyl)oxy)methyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3i)

t-Butyl 2-(Diphenyl((trimethylsilyl)oxy)methyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (3j)

Methyl (2S*,3S*)-2-(Diphenyl((trimethylsilyl)oxy)methyl)-3-methyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (cis-3k)

Ethyl 4-(Diphenyl((trimethylsilyl)oxy)methyl)-8-methoxyquinoline-3-carboxylate (13a)

Ethyl 4-(Diphenyl((trimethylsilyl)oxy)methyl)-5,8-dimethoxyquinoline-3-carboxylate (13b)

Ethyl 4-(Diphenyl((trimethylsilyl)oxy)methyl)-6,8-dimethoxyquinoline-3-carboxylate (13c)

Desilylation of 3 with TBAF

3,3-Diphenyl-3a,4-dihydro-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (5a)

3,3-Bis(4-fluorophenyl)-3a,4-dihydro-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (5b)

3a,4-Dihydro-1H,5H-spiro[oxazolo[3,4-a]quinoline-3,9′-xanthene]-1,5-dione (5c)

3a′,4′,10,11-Tetrahydro-1′H,5′H-spiro[dibenzo[a,d][7]annulene-5,3′-oxazolo[3,4-a]quinoline]-1′,5′-dione (5d)

3a′,4′-Dihydro-1′H,5′H-spiro[dibenzo[a,d][7]annulene-5,3′-oxazolo[3,4-a]quinoline]-1′,5′-dione (5e)

3a′,4′-Dihydro-1′H,5′H-spiro[fluorene-9,3′-oxazolo[3,4-a]quinoline]-1′,5′-dione (5f)

(3aS*,4S*)-4-Methyl-3,3-diphenyl-3a,4-dihydro-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (cis-5g)

(3aS*,4R*)-4-Methyl-3,3-diphenyl-3a,4-dihydro-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (trans-5f)

6-Methoxy-1,1-diphenylfuro[3,4-c]quinolin-3(1H)-one (14a)

6,9-Dimethoxy-1,1-diphenylfuro[3,4-c]quinolin-3(1H)-one (14b)

6,8-Dimethoxy-1,1-diphenylfuro[3,4-c]quinolin-3(1H)-one (14c)

Desilylation of 3 with 1 M HCl Aqueous (aq) and Dioxane

Methyl 2-(Hydroxydiphenylmethyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (4b)

Cyclization of 4b

Transformation of 3h to 7a

2-Benzhydrylquinolin-4(1H)-one (7a)

2-(Bis(4-fluorophenyl)methyl)quinolin-4(1H)-one (7b)

Dehydrogenation of 5 with DDQ

3,3-Diphenyl-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (8a)

3,3-Bis(4-fluorophenyl)-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (8b)

Table 1. Electroreductive Coupling of 1-Alkoxycarbonyl-4-quinolones 1b–d with 2a–f^a.

Table 9. E_p values of 1a–n and 2a–f Derived from CV at 25 °C.

Methyl (2S,3S)-2-(Diphenyl((trimethylsilyl)oxy)methyl)-3-methyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (cis-3k)

(3aS,4S)-4-Methyl-3,3-diphenyl-3a,4-dihydro-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (cis-5g)

(3aS,4R)-4-Methyl-3,3-diphenyl-3a,4-dihydro-1H-oxazolo[3,4-a]quinoline-1,5(3H)-dione (trans-5f)

run	3	5	% yield^a
1	3b	5a	89
2	3c	5b	87
3	3d	5c	75
4	3e	5d	88
5	3f	5e	83
6	3g	5f	92
7	3h	5a	85
8	3i	5b	81
9	3j	5a	84