Novel synthesis and cytotoxic activity of 1,4-disubstituted 3-methylidene-3,4-dihydroquinolin-2(1H)-ones

Abstract

A novel, efficient synthesis of 1,4-disubstituted 3-methylidene-3,4-dihydrodihydroquinolin-2(1H)-ones was accomplished via a three step reaction sequence comprising N-alkylation of 3-diethoxyphosphorylquinolin-2(1H)-one, Michael addition of various Grignard reagents to N-alkylated 3-diethoxyphosphorylquinolin-2(1H)-ones and a Horner–Wadsworth–Emmons reaction of the obtained adducts with formaldehyde. Effective synthesis of the starting 3-diethoxyphosphorylquinolin-2(1H)-one was also developed. Furthermore, the obtained 3-methylidene-3,4-dihydroquinolin-2(1H)-ones were evaluated for their cytotoxic activity.

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Introduction

α-Alkylidene-γ or δ-lactones 1 and the corresponding α-alkylidene-γ and δ-lactams 2 are a big class of natural as well as synthetic compounds that display a broad spectrum of biological properties (Fig. 1).^1,2 It is generally believed that the conjugated α-alkylidene moiety incorporated onto the lactone or lactam ring is crucial for their biological activities.³ Undoubtedly, α-alkylidene-γ-lactones constitute the biggest and the best known group within this class. On the other hand, α-alkylidene-δ-lactams are much less recognized and only recently was the first natural humantenine-type alkaloid containing this moiety, gelegamine B 3, isolated from Gelsemium elegan, a liane growing in Southeast Asia.⁴ On the other hand, many synthetic α-alkylidene-δ-lactams are known, however, their biological activity is hardly recognized.² In our search for new, biologically active heterocycles we turned our attention to 3-alkylidene-3,4-dihydroquinolin-2(1H)-ones 4, containing α-alkylidene-δ-lactam moiety.

Fig. 1 Structures of α-alkylidene-γ and δ-lactons and lactams.

A literature survey revealed that 3-alkylidene-3,4-dihydroquinolin-2(1H)-ones 4 were usually synthesized using Baylis–Hillman derivatives as starting material. When Baylis–Hillman acetates were subjected to nucleophilic substitution using anilines, followed by PPA-mediated Claisen rearrangement and lactamization of the obtained products, 3-arylmethylidenedihydroquilolin-2(1H)-ones were formed in good to moderate yields.⁵ In an interesting variation of this method, TFA was used as a promoter of the Claisen rearrangement instead of PPA.⁶ Another approach starts with Baylis–Hillman acids which are transformed into corresponding amides followed by a H₂SO₄-catalyzed intramolecular Friedel–Crafts reaction. This method gives 4-substituted 3-methylidenedihydroquinolin-2-ones in moderate yields.⁷ Other synthetic approaches to specific 3-methylidenedihydroquinolin-2-ones were also reported. 4-(1-Nitroethyl)-3-methylidene-3,4-dihydroquinolin-2(1H)-one and its 5-chloro analogue were prepared from the corresponding 3-aryl-2-methylidene-4-nitroalkanoates.⁸ 6-Benzoil- and 6-metoxycarbonyl-1-methyl-3-methylidene-3,4-dihydroquinolin-2(1H)-ones were synthesized from methacrylanilides by photochemical electrocyclic ring closure followed by the elimination of the allylic leaving group.⁹ Finally, unsubstituted 3-methylidene-3,4-dihydroquinolin-2(1H)-one was prepared applying one pot reduction-lactamization sequence to 2-(2-nitrobenzyl)acrylate.¹⁰ Surprisingly, to the best of our knowledge, there are no reports on the biological activity of 3-alkylidene-3,4-dihydroquinolin-2(1H)-ones 4.

In this report we describe novel synthesis of 1,4-disubstituted 3-methylidene-3,4-dihydroquinolin-2(1H)-ones 20 based on the Horner–Wadsworth–Emmons approach to α-alkylidenelactons and lactams, well recognized in our laboratory.¹¹ Furthermore, we tested the obtained methylidenequinolinones 20 for their cytotoxic activity against two human leukemia cell lines HL-60 and NALM-6 as well as the MCF-6 breast cancer cell line.

Results and discussion

We started our synthesis with the preparation of 3-diethoxyphosphorylquinolin-2(1H)-one 8 as a crucial intermediate. This compound was unknown so far, but the synthesis of 7-substituted 3-diethoxyphosphorylquinolin-2-ones, from 4-substituted 2-aminobenzaldehydes and diethoxyphosphorylacetyl chloride, was described in the literature.¹² Applying the literature conditions (toluene as solvent, 1.2 mol. equivalent of pyridine, rt, 45 min.) we performed the reaction of 2-aminobenzaldehyde 5 with diethoxyphosphorylacetyl chloride 6. Disappointingly, the intermediate amide 7 was formed in very low, 15% yield. However, further cyclization of the amide 7 to 8 occurred in excellent, 89% yield (Scheme 1).

Scheme 1 Reagents and conditions: (a) 2,6-lutidine, toluene, 0 °C, 45 min.; (b) piperidine, toluene, reflux, 8 h.

To obtain the amide 7 in a reasonable yield we performed an optimization of its synthesis changing solvents, bases and temperature. However, even in the optimized conditions (toluene, 1.2 mol. equivalent of 2,6-lutidine, 0 °C, 45 min.) the yield of 7 did not exceed 49%. Interestingly, during the optimization we noticed the formation of a considerable amount of a side product, which became the main product when the reaction was performed at room temperature and for a prolonged period of time (2.5 h). Chromatographic isolation and careful analysis of NMR spectra as well as MS data of this side product enabled us to determine its structure as a complex diphosphonate 9. The formation of 9, although puzzling at first, can be rationalized assuming a multicomponent reaction between three molecules of 2-aminobenzaldehyde 5 and two molecules of diethoxyphosphorylacetyl chloride 6. The likely mechanism of this reaction is shown in Scheme 2. The initially formed amide 7 can react with 10, which is the autocondesation product of two molecules of 2-aminobenzaldehyde, to give imine 11. Next, intramolecular cyclization yields tricyclic alcohol 12, which is finally acylated by a second molecule of chloride 6 to give diphosphonate 9. Similar reactions furnishing the core tricyclic structure present in 12, by trimerization of 2-aminobenzaldehyde 5, are described in the literature.¹³

Scheme 2 Proposed mechanism for the formation of diphosphonate 9.

Low efficiency of the synthesis of our crucial intermediate – 3-diethoxyphosphorylquinolin-2(1H)-one 8 (44% overall yield, starting from 5), prompted us to search for new, more effective method. As we had hoped, Knoevenagel condensation of o-nitrobenzaldehyde 13 with ethyl diethoxyphosphorylacetate 14 gave ethyl 2-diethoxyphosphoryl-3-(2-nitrophenyl)acrylate 15 in 92% yield, as a mixture of E and Z isomers, in a 88 : 12 ratio (Scheme 3). The reduction of the nitro group and the subsequent intramolecular cyclization furnished the expected 3-diethoxyphosphorylquinolin-2-one 8 in 85% yield (78% overall yield, starting from 13).

Scheme 3 Reagents and conditions: (a) TiCl₄, N-methylmorpholine, CCl₄, THF, 0 °C to rt, 5 h; (b) Fe dust, AcOH, 6 h.

With the efficient synthesis of 8 in hand we started a three step synthesis of 3-methylidenedihydroquinolin-2-ones 20. Treatment of 8 with various alkyl iodides or bromides in the presence of NaH lead to the mixtures of N- and O-alkylation products 16 and 17, respectively (Scheme 4). The ratios of N- to O-alkylation products are given in Table 1. Pleasingly, the mixtures were easily separated using column chromatography and pure N-alkylated quinolin-2-ones 16a-d were obtained in reasonable yields (Table 1). We also were able to purify and characterize three O-alkylation products 17b-d. Other bases, such as K₂CO₃, CsCO₃ or DIPEA were also tested but performing the reaction in the presence of NaH led to the best ratio of N- to O-alkylated products.

Scheme 4 Reagents and conditions: (a) alkyl halide, NaH, DMF, rt, 6–24 h.

Table 1 Synthesis of 1-alkyl-3-diethoxyphosphorylquinolin-2-ones 16a-d and 2-alkoxy-3-diethoxyphosphorylquinolines 17b-d

Compound	Alkyl halide	16/17 ratio^a	16^b yield [%]	17^b yield [%]
a Taken from the ^31P NMR spectrum of the crude product.b Yield of isolated, purified product, based on 8.
a	MeI	>95:5	66	—
b	EtI	85:15	61	14
c	n-BuI	80:20	59	13
d	BnBr	85:15	70	10

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In the next step N-alkylated quinolin-2-ones 16a-d were used as Michael acceptors in reactions with various Grignard reagents (Scheme 5). The additions proceeded smoothly in THF at room temperature yielding 1,4-disubstituted 3-diethoxyphosphoryl-3,4-dihydroquinolin-2(1H)-ones 18a-o, as a single trans isomers or as a mixture of trans and cis isomers (Table 2). However, after the purification of the crude products by column chromatography only trans-18a-o were isolated and characterized (Table 2). Configurational assignments were made on the bases of diagnostic ³J_H3H4 coupling constants which fell in the range between 1.0 Hz and 1.4 Hz for all trans isomers. Similar coupling constants, characteristic for trans diaxial arrangement of diethoxyphosphoryl group and substituent in position 4 were observed in trans-4-substituted-3-diethoxyphosphorylchroman-2-ones.¹⁴ Furthermore, from the ¹H NMR spectrum of the mixture of trans- and cis-18d it was possible to determine ³J_H3H4 = 4.8 Hz for cis-18d what confirmed the correctness of assignments. It is noteworthy, that additions of phenylmagnesium chloride proceeded more effectively in the presence of a catalytic amount of Cu₂I₂ (see Table 2). Surprisingly, additions performed with isopropylmagnesium chloride gave considerable amount (19–41%) of dephosphorylated side products 19b,f,i,m (Fig. 2). These products were also separated and purified. One can speculate that the driving force for the elimination of diethoxyphosphoryl moiety from quinolinones 18b,f,i,m might be the release in steric repulsion between diethoxyphosphoryl and vicinal isopropyl groups. However, the mechanism of the formation of dephosphorylated quinolin-2-ones 19 is unclear and its explanation needs further investigation.

Scheme 5 Reagents and conditions: (a) Grignard reagent, THF, rt, 2 h; (b) paraformaldehyde, NaH, THF, rt, 4 h.

Table 2 Synthesis of 3-diethoxyphosphorylquinolin-2(1H)-ones 18a-o and 3-methylidene-3,4-dihydroquinolin-2(1H)-ones 20a-m,o

Compound	R^1	R^2	18 trans/cis ratio^a	trans-18^b yield [%]	20^b yield [%]
a Taken from the ^31P NMR spectrum of the crude product.b Yield of isolated, purified product, based on 16 or 18, respectively.c In the presence of 0.1 equivalent of Cu2I2.d Compound 20c is known (ref. 7).
a	Me	Et	>95 : 5	73	82
b	Me	i-Pr	93 : 7	43	87
c	Me	Ph	>95 : 5	52/75^c	90^d
d	Et	Me	75 : 25	56	80
e	Et	Et	>95 : 5	88	92
f	Et	i-Pr	>95 : 5	50	89
g	Et	Ph	>95 : 5	45/65^c	73
h	n-Bu	Et	>95 : 5	85	92
i	n-Bu	i-Pr	>95 : 5	41	91
j	n-Bu	Ph	>95 : 5	57/91^c	94
k	Bn	Me	80 : 20	54	94
l	Bn	Et	>95 : 5	58	96
m	Bn	i-Pr	92 : 8	65	91
n	Bn	Vinyl	>95 : 5	21	—
o	Bn	Ph	>95 : 5	58/79^c	83

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Fig. 2 General structure of the dephosphorylated side products 19b,f,i,m.

Finally, the 3-diethoxyphosphoryl-3,4-dihydroquinolin-2(1H)-ones 18a-o were used in the Horner–Wadsworth–Emmons olefination of formaldehyde. Thus, the treatment of 18 with NaH and then with paraformaldehyde gave, after purification by column chromatography, 3-methylidene-3,4-dihydroquinolin-2(1H)-ones 20a-m,o, in very good yields (Table 2) and their structures were unequivocally confirmed by spectroscopic methods. Only the olefination of 3-diethoxyphosphoryl-4-vinyl-3,4-dihydroquinolin-2(1H)-one 18n was inefficient and gave a mixture of products difficult to separate and purify. However, ¹H NMR spectrum of partially purified reaction mixture revealed signals which could be attributed to 1-benzyl-3-methyl-4-vinylquinolin-2(1H)-one, apparently originated from the isomerization of the initially formed 3-methylidene-3,4-dihydroquinolin-2(1H)-one 20n.

Evaluation of cytotoxicity

The obtained 3-methylidene-3,4-dihydroquinolin-2(1H)-ones 20a-m,o were tested in vitro against three human cancer cell lines: leukemia NALM-6 and HL-60 as well as breast cancer MCF-7 and the results are shown in Table 3. Carboplatin was used as a reference compound.¹⁵ In general, cytotoxicities of all these compounds are moderate or low, with IC₅₀ values ranging from 40.2 μM (25b, against MCF-7 cells) to 405 μM (25l, against HL-60 cells) and no significant differences between cell lines were observed. However, the activity of the specific compound depends significantly on the nature of substituents in positions 1 and 4. Moderate activity, with IC₅₀ values below 100 μM against all three cell lines display compounds 20h-m,o with n-butyl or benzyl substituent in position 1. The only exception is quinolinone 20l which has low cytotoxicity against all three cell lines. On the other hand phenyl is definitely the best substituent in position 4. All four 4-phenylquinolinones 20c,g,j,o are among the most active compounds and have IC₅₀ values in the range between 40 μM and 100 μM against all three cancer cell lines tested.

Table 3 In vitro cytotoxic activity of 3-methylidene-3,4-dihydroquinolin-2(1H)-ones 20a-m,o

Compound 20	R^1	R^2	IC50^a (μM)
			HL-60	NALM-6	MCF-7
a Compound concentration required to inhibit tumor cell proliferation by 50%. Data are expressed as the mean ± SD from the concentration–response curves of at least three experiments.
a	Me	Et	228 ± 19	238 ± 15	216±18
b	Me	i-Pr	183 ± 12	331 ± 22	40.2 ± 3.1
c	Me	Ph	69.9 ± 3.2	61.0 ± 3.9	100 ± 6.4
d	Et	Me	304 ± 15	289 ± 33	156 ± 22
e	Et	Et	114 ± 16	166 ± 19	233 ± 29
f	Et	i-Pr	128 ± 13	96.7 ± 4.2	70.3 ± 5.8
g	Et	Ph	61.5 ± 3.5	54.0 ± 5.4	60.2 ± 4.8
h	n-Bu	Et	60.3 ± 7.2	72.7 ± 5.8	88.3 ± 7.7
i	n-Bu	i-Pr	75.9 ± 7.4	58.7 ± 3.6	65.3 ± 4.7
j	n-Bu	Ph	55.4 ± 2.6	47.2 ± 5.8	70.3 ± 5.7
k	Bn	Me	66.4 ± 4.5	61.5 ± 6.6	72.9 ± 4.4
l	Bn	Et	405 ± 33	96.6 ± 4.2	200 ± 17
m	Bn	i-Pr	61.3 ± 5.4	54.4 ± 5.6	101 ± 15
o	Bn	Ph	48.0 ± 4.9	43.6 ± 4.1	74.3 ± 6.9
Carboplatin	—	—	2.9 ± 0.1	0.7 ± 0.3	3.8 ± 0.45

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Conclusions

We have developed simple, general and efficient method for the synthesis of biologically important 3-methylidenedihydroquinolin-2-ones 20 with various substituents in positions 1 and 4. Contrary to the reported so far methods, which are based on Baylis–Hillman derivatives, our synthesis starts with easily available 3-diethoxyphosphorylquinolin-2-one 8, which is N-alkylated and next subjected to Michael addition of Grignard reagents to give 1,4-disubstituted 3-diethoxyphosphorylquinolin-2-ones 18. In the last step, final 3-methylidenedihydroquinolin-2-ones 20 are synthesized using Horner–Wadsworth–Emmons methodology. During the search for the efficient synthesis of starting 3-diethoxyphosphorylquinolin-2-one 8, we elaborated the structure of the complex diphosphonate 9 which was formed as a side product in the reaction of 2-aminobenzaldehyde 5 with diethoxyphosphorylacetyl chloride 6. Eventually, we developed simple and effective synthesis of 8 from o-nitrobenzaldehyde 13 and ethyl diethoxyphosphorylacetate 14. Furthermore, cytotoxic activity of the final 3-methylidenedihydroquinolin-2-ones 20 was tested in vitro against three human cancer cell lines and compounds with n-butyl or benzyl substituent in position 1 and phenyl substituent in position 4 were found to possess the best cytotoxicity, with IC₅₀ values in the range of 40 to 100 μM. It is worth to stress that cytotoxicity of 3-methylidenedihydroquinolin-2-ones have not been so far evaluated.

Experimental section

General

NMR spectra were recorded on a Bruker DPX 250 or Bruker Avance II instrument at 250.13 MHz or 700 MHz for ¹H, 62.9 MHz or 176 MHz for ¹³C, and 101.3 MHz for ³¹P NMR using tetramethylsilane as internal and 85% H₃PO₄ as external standard. ³¹P NMR spectra were recorded using broadband proton decoupling. IR spectra were recorded on a Bruker Alpha ATR spectrophotometer. Melting points were determined in open capillaries and are uncorrected. Column chromatography was performed on Aldrich® silica gel 60 (230–400 mesh). Thin-layer chromatography was performed with precoated TLC sheets of silica gel 60 F₂₅₄ (Aldrich®). The purity of tested compounds was determined by combustion elemental analyses (CHN, elemental analyzer EuroVector 3018, Elementar Analysen systeme GmbH). MS spectra were performed on combined Waters 2695-Waters ZQ 2000 LC/MS apparatus. Reagents and starting materials were purchased from commercial vendors and used without further purification. All organic solvents were dried over appropriate drying agents and distilled prior to use. Standard syringe techniques were used for transferring dry solvents.

Synthesis of 3-diethoxyphosphorylquinolin-2(1H)-one 8

Synthesis of 3-diethoxyphosphorylquinolin-2(1H)-one 8 from o-aminobenzaldehyde (5).
Synthesis of diethyl [(2-formylphenyl)carbamoyl]methylphosphonate (7). To a solution of 2-aminobenzaldehyde 5 (0.434 g, 4.00 mmol) and 2,6-lutidine (0.428 g, 4.00 mmol) in toluene (5 mL) under nitrogen atmosphere a solution of diethyl 2-chloro-2-oxoethylphosphonate 6 (0.858 g, 4.00 mmol) in toluene (5 mL) was added dropwise maintaining the temperature below 0 °C. When the addition was completed, the mixture was stirred at room temperature for 45 min. The mixture was washed with H₂O (10 mL) and brine (10 mL) and dried over MgSO₄. The solvent was removed in vacuo to yield a crude product which was purified by column chromatography (eluent : toluene/EtOAc 4/1). Yellow oil was obtained (0.587 g, 49%). Rf: 0.2 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 3259, 2982, 1667, 1609, 1587, 1526, 1247, 1046. ³¹P NMR (101 MHz, CDCl₃) δ 20.82 ppm. ¹H NMR (250 MHz, CDCl₃) δ 11.30 (s, 1H), 9.91 (d, J = 0.7 Hz, 1H), 8.69 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 7.7, 1.6 Hz, 1H), 7.63–7.55 (m, 1H), 7.24 (dt, J = 7.6, 1.0 Hz, 1H), 4.28–4.12 (m, 4H), 3.08 (d, J = 21.6 Hz, 2H), 1.33 (td, J = 7.0, 0.5 Hz, 6H). ¹³C NMR (63 MHz, CDCl₃) δ 194.12, 162.75 (d, J = 6.1 Hz), 139.35, 135.05, 134.89, 122.34, 120.87, 119.06, 61.82 (d, J = 6.4 Hz), 37.29 (d, J = 131.4 Hz), 15.32 (d, J = 6.0 Hz). Anal. calcd for C₁₃H₁₈NO₅P: C, 52.18; H, 6.06; N, 4.68. Found: C, 52.30; H, 6.08; N, 4.66%.

Along with diethyl [(2-formylphenyl)carbamoyl]methylphosphonate (7) also diphosphonate 9 was isolated by column chromatography.

(8,16,24)-9-[2-(Diethoxyphosphoryl)acetyl]-1,9,17-triazahexacyclo[14.8.0.0^2,7.0^8,17.0^10,15.0^18,23]tetracosa-2(7),3,5,10(15),11,13,18(23),19,21-nonaen-24-yl 2-(diethoxyphosphoryl)acetate (9). Off-white solid mp 116–118 °C. Rf: 0.3 (UV active, CH₂Cl₂ : EtOAc = 1 : 2). IR (neat) ν (cm⁻¹): 2982, 2926, 1740, 1667, 1482, 1371, 1228, 1112, 1017, 966. ³¹P NMR (101 MHz, CDCl₃) δ 19.87, 21.11 ppm. ¹H NMR (250 MHz, DMSO-d₆, 333K) δ 1.08–1.25 (m, 12H), 3.24 (dd, J = 21.5, 2.4 Hz, 1H), 3.33 (dd, J = 21.2, 14.6 Hz, 1H), 3.59 (d, J = 21.6 Hz, 2H), 3.90–4.18 (m, 8H), 5.45 (s, 1H), 6.47 (s, 1H), 6.52 (s, 1H), 6.87 (ddd, J = 7.6, 5.9, 2.6 Hz, 1H), 6.99–7.23 (m, 8H), 7.32 (m, 2H), 7.49 (ddd, J = 10.0, 8.0, 1.4 Hz, 2H). ¹³C NMR (63 MHz, CDCl₃) δ 16.37, 16.46, 16.54, 34.32 (d, J = 136.3 Hz), 34.98 (d, J = 132.6 Hz), 62.76, 63.03, 63.13, 63.23, 65.27, 67.91, 85.10, 123.48, 124.19, 124.43, 125.05, 125.63, 125.71, 127.22, 128.15, 128.95, 129.31, 129.65, 130.23, 136.28, 141.91, 144.34, 165.09 (d, J = 6.7 Hz), 165.39. ESI-MS [M + H]⁺ = 684; [M − H]⁻ = 682. Anal. calcd for C₁₃H₁₆NO₄P: C, 57.98; H, 5.75; N, 6.15. Found: C, 57.77; H, 5.76; N, 6.12%.
Synthesis of ethyl (2-oxo-1,2-dihydroquinolin-3-yl)phosphonate (8). Diethyl [(2-formylphenyl)carbamoyl]methylphosphonate 7 (1.20 g, 4.00 mmol) was dissolved in dry toluene (12 mL) in argon atmosphere and then piperidine (0.029 g, 0.40 mmol) was added. The mixture was stirred in Dean–Stark apparatus for 8 hours at reflux. Than it was condensed in vacuo and the residue was triturated with Et₂O to give off-white solid (1.00 g, 89%) mp 170–172 °C. Rf: 0.3 (UV active, CH₂Cl₂ : EtOAc = 1 : 2). IR (neat) ν (cm⁻¹): 3165, 2984, 1648, 1474, 1054, 1222, 1022, 968. ³¹P NMR (101 MHz, CDCl₃) δ 14.52 ppm. ¹H NMR (250 MHz, CDCl₃) δ 12.63 (s, 1H), 8.59 (d, J = 17.6 Hz, 1H), 7.64 (dd, J = 7.9, 1.3 Hz, 1H), 7.61–7.52 (m, 1H), 7.50–7.42 (m, 1H), 7.28–7.18 (m, 1H), 4.43–4.19 (m, 4H), 1.38 (td, J = 7.1, 0.6 Hz, 6H). ¹³C NMR (63 MHz, CDCl₃) δ 162.51 (d, J = 11.6 Hz), 150.52 (d, J = 6.7 Hz), 140.47, 132.86, 129.17, 122.95, 121.17 (d, J = 194.9 Hz), 118.73 (d, J = 15.8 Hz), 116.21, 62.90 (d, J = 5.8 Hz), 16.46 (d, J = 6.5 Hz). ESI-MS [M + H]⁺ = 282; [M − H]⁻ = 280. Anal. calcd for C₁₃H₁₆NO₄P: C, 55.52; H, 5.73; N, 4.98. Found: C, 55.46; H, 5.77; N, 4.96%.

Synthesis of 3-diethoxyphosphorylquinolin-2(1H)-one 8 from o-nitrobenzaldehyde (13).
Synthesis of ethyl 2-(diethoxyphosphoryl)-3-(2-nitrophenyl)prop-2-enoate (15). To dry THF (60 mL) in argon atmosphere at 0 °C the solution of TiCl₄ (5.04 mL, 45.65 mmol) in CCl₄ (15 mL) was added dropwise followed by the ethyl diethoxyphosphorylacetate (5.16 g, 22.83 mmol) and N-methylmorpholine (9.54 g, 94.30 mmol). It was stirred for 30 min at 0 °C and then the solution of 2-nitrobenzaldehyde 13 (3.0 g, 19.85 mmol) in THF (15 mL) was added portionwise. The reaction mixture was slowly warmed to rt and stirred for 4 h. Then water was added (100 mL) and the mixture was extracted with Et₂O (2 × 80 mL). Combined organic layers were washed with brine, dried over MgSO₄ and evaporated under reduced pressure, affording the crude product that was purified by column chromatography (eluent : CH₂Cl₂/EtOAc 5/1). Yellow oil was obtained (6.02 g, 92%) as the mixture of E and Z isomers. Analytical data for ethyl (E)-2-(diethoxyphosphoryl)-3-(2-nitrophenyl)prop-2-enoate (15): Rf: 0.7 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 3467, 2983, 1719, 1602, 1523, 1369, 1250, 1014, 971. ³¹P NMR (101 MHz, CDCl₃) δ 12.91 ppm. ¹H NMR (250 MHz, CDCl₃) δ 8.22 (dd, J = 8.1, 1.5, 1H), 8.19 (d, J = 21.4 Hz, 1H), 7.65 (ddd, J = 7.5, 7.4, 1.5, 1H), 7.55 (ddd, J = 8.1, 7.5, 1.1, 1H), 7.35 (dd, J = 7.4, 1.1, 1H), 4.26 (m, 4H), 4.03 (q, J = 7.1 Hz, 2H), 1.39 (td, J = 7.1, 0.7 Hz, 6H), 1.00 (t, J = 7.1 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 164.05 (d, J = 13.6 Hz), 149.21 (d, J = 8.0 Hz), 146.39, 133.60, 131.63 (d, J = 20.3 Hz), 129.73, 129.63 (d, J = 2.4 Hz), 126.67 (d, J = 180.5 Hz), 124.55, 62.94 (d, J = 5.5 Hz), 61.25, 16.11 (d, J = 6.4 Hz), 13.49. ESI-MS [M + H]⁺ = 358; [M + Na]⁺ = 380. Anal. calcd for C₁₅H₂₀NO₇P: C, 50.42; H, 5.64; N, 3.92. Found: C, 50.60; H, 5.64; N, 3.83%.
Synthesis of ethyl (2-oxo-1,2-dihydroquinolin-3-yl)phosphonate (8). Ethyl 2-(diethoxyphosphoryl)-3-(2-nitrophenyl)prop-2-enoate 15 (1.43 g, 4.00 mmol) was dissolved in acetic acid (15 mL) and then to the intensively stirred solution reduced iron powder (1.34 g, 24.00 mmol) was added. The mixture was warmed to 80 °C and stirred for 6 hours. Then it was filtered through celite cake and the solid residue was washed with acetic acid (15 mL) and EtOAc (15 mL). The filtrate was evaporated. The dark residue was dissolved in EtOAc (15 mL) and washed with 5% NaHCO₃ (2 × 15 mL), then with water (10 mL) and brine (10 mL) and dried over Na₂SO₄. Obtained brown solid was purified by column chromatography on silica gel (eluent : EtOAc/CH₂Cl₂ 1/1) to give 3-diethoxyphosphorylquinolin-2-one 8 (0.956 g, 85%).

General procedure for the synthesis of 1-alkyl-3-diethoxyphosphorylquinolin-2-ones 16a-d

To the solution of 3-diethoxyphosphorylquinolin-2-one 8 (1.41 g, 5.0 mmol) in DMF (15 mL) under argon atmosphere, provided with water bath, 80% sodium hydride (0.165 g, 5.5 mmol) was added portionwise. The reaction mixture was stirred for 10 min. Then the alkyl halide (6.0 mmol) was added in one portion and the reaction mixture was stirred at rt overnight (for 16d) or for 8 h (for 16c) or for 6 h (for 16a-b). Then solvent was removed under reduced pressure and the residue was separated between ethyl acetate (25 mL) and water (25 mL). The water layer was extracted with the second portion of ethyl acetate (25 mL). Combined organic layers were washed with brine, dried over MgSO₄ and evaporated under reduced pressure, affording the crude product that was purified by column chromatography (eluent : CH₂Cl₂/EtOAc). For 1-alkyl-3-diethoxyphosphorylquinolin-2-ones 17b-d also O-alkylation products were isolated and characterized.

Diethyl (1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)phosphonate (16a). White solid (0.974 g, 66%) mp 50–52 °C. Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.4 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 3042, 2980, 2906, 1729, 1638, 1588, 1474, 1418, 1162, 1049, 1019, 966. ³¹P NMR (101 MHz, CDCl₃) δ 14.55 ppm. ¹H NMR (250 MHz, CDCl₃) δ 8.47 (d, J = 17.6 Hz, 1H), 7.65 (m, 2H), 7.35 (d, J = 9.0 Hz, 1H), 7.26 (m, 1H), 4.41–4.14 (m, 4H), 3.71 (s, 3H), 1.48–1.29 (m, 6H). ¹³C NMR (63 MHz, CDCl₃) δ 159.84 (d, J = 12.0 Hz), 148.20 (d, J = 6.5 Hz), 141.16, 132.79, 130.01, 122.22, 121.03 (d, J = 196.9 Hz), 118.86 (d, J = 16.5 Hz), 113.97, 62.62 (d, J = 6.0 Hz), 29.17, 16.18 (d, J = 6.2 Hz). ESI-MS [M + H]⁺ = 296; [M + Na]⁺ = 318. Anal. calcd for C₁₄H₁₈NO₄P: C, 56.95; H, 6.14; N, 4.74. Found: C, 57.05; H, 6.15; N, 4.73%.

Diethyl (1-ethyl-2-oxo-1,2-dihydroquinolin-3-yl)phosphonate (16b). Yellow oil (0.943 g, 61%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.4 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2979, 1638, 1616, 1562, 1449, 1242, 1219, 1049, 1019. ³¹P NMR (101 MHz, CDCl₃) δ 14.67 ppm. ¹H NMR (250 MHz, CDCl₃) δ 8.45 (d, J = 17.5 Hz, 1H), 7.68–7.61 (m, 2H), 7.37 (d, J = 9.0 Hz, 1H), 7.29–7.21 (m, 1H), 4.41–4.19 (m, 6H), 1.37 (td, J = 7.1, 0.4 Hz, 6H), 1.36 (t, J = 7.2 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 159.59 (d, J = 12.2 Hz), 148.34 (d, J = 6.5 Hz), 140.40, 132.90, 130.46, 122.18, 121.16 (d, J = 197.4 Hz), 119.37 (d, J = 16.5 Hz), 113.96, 62.86 (d, J = 6.1 Hz), 37.39, 16.33 (d, J = 6.2 Hz), 12.47. ESI-MS [M + H]⁺ = 310; [M + Na]⁺ = 332. Anal. calcd for C₁₅H₂₀NO₄P: C, 58.25; H, 6.52; N, 4.53. Found: C, 58.33; H, 6.54; N, 4.51%.

Diethyl (2-ethoxyquinolin-3-yl)phosphonate (17b). Yellow oil (0.216 g, 14%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2980, 2931, 2905, 1618, 1592, 1416, 1338, 1252, 1074, 1019. ³¹P NMR (101 MHz, CDCl₃) δ 15.16 ppm. ¹H NMR (250 MHz, CDCl₃) δ 8.66 (dd, J = 16.2, 0.7 Hz, 1H), 7.84–7.75 (m, 2H), 7.69 (ddd, J = 8.4, 6.9, 1.6 Hz, 1H), 7.40 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.33–4.07 (m, 4H), 1.47 (t, J = 7.1 Hz, 3H), 1.36 (td, J = 7.0, 0.6 Hz, 6H). ¹³C NMR (63 MHz, CDCl₃) δ 160.57 (d, J = 5.3 Hz), 148.32, 147.42 (d, J = 7.0 Hz), 131.75, 128.50, 126.97, 124.53, 123.80 (d, J = 12.3 Hz), 113.23 (d, J = 190.0 Hz), 62.55 (d, J = 5.6 Hz), 62.29, 16.37 (d, J = 6.3 Hz), 14.44. ESI-MS [M + H]⁺ = 310, [M + Na]⁺ = 332. Anal. calcd for C₁₅H₂₀NO₄P: C, 58.25; H, 6.52; N, 4.53. Found: C, 58.10; H, 6.54; N, 4.51%.

Diethyl (1-butyl-2-oxo-1,2-dihydroquinolin-3-yl)phosphonate (16c). White solid (0.995 g, 59%) mp 89–90 °C. Chromatography (CH₂Cl₂/EtOAc 8/1). Rf: 0.5 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2961, 1630, 1586, 1562, 1451, 1237, 1057, 1026, 940. ³¹P NMR (101 MHz, CDCl₃) δ 14.77 ppm. ¹H NMR (250 MHz, CDCl₃) δ 8.45 (d, J = 17.6, 1H), 7.64 (m, 2H), 7.34 (d, J = 8.9 Hz, 1H), 7.28–7.20 (m, 1H), 4.40–4.15 (m, 6H), 1.78–1.65 (m, 2H), 1.55–1.42 (m, 2H), 1.36 (td, J = 7.1, 0.6 6H), 0.97 (t, J = 7.5 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 159.84 (d, J = 11.7 Hz), 148.50, 140.77, 132.86, 130.50, 122.19, 121.39 (d, J = 196.3 Hz), 119.46 (d, J = 16.5 Hz), 114.17, 62.89 (d, J = 6.1 Hz), 42.31, 29.36, 20.21, 16.42 (d, J = 6.2 Hz), 13.76. ESI-MS [M + H]⁺ = 338; [M + Na]⁺ = 360. Anal. calcd for C₁₇H₂₄NO₄P: C, 60.53; H, 7.17; N, 4.15. Found: C, 60.39; H, 7.20; N, 4.13%.

Diethyl (2-butoxyquiolin-3-yl)phosphonate (17c). Colourless oil (0.219 g, 13%). Chromatography (CH₂Cl₂/EtOAc 8/1). Rf: 0.7 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2959, 2933, 2872, 1618, 1592, 1415, 1341, 1251, 1074, 1020, 957. ³¹P NMR (101 MHz, CDCl₃) δ 15.46 ppm. ¹H NMR (250 MHz, CDCl₃) δ 8.67 (dd, J = 16.3, 0.7 Hz, 1H), 7.84–7.74 (m, 2H), 7.69 (ddd, J = 8.5, 6.9, 1.6, 1H), 7.40 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 4.56–4.51 (m, 2H), 4.32–4.05 (m, 4H), 1.94–1.75 (m, 2H), 1.65–1.48 (m, 2H), 1.38–1.28 (m, 6H), 0.99 (t, J = 7.3 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 160.84 (d, J = 5.2 Hz), 148.44, 147.67 (d, J = 7.3 Hz), 131.83, 128.59, 127.00, 124.56, 123.85 (d, J = 12.5 Hz), 113.14 (d, J = 190.0 Hz), 66.26, 62.50 (d, J = 5.6 Hz), 31.01, 19.23, 16.39 (d, J = 6.4 Hz), 13.85. ESI-MS [M + H]⁺ = 338, [M + Na]⁺ = 360. Anal. calcd for C₁₇H₂₄NO₄P: C, 60.53; H, 7.17; N, 4.15. Found: C, 60.52; H, 7.20; N, 4.16%.

Diethyl (1-benzyl-2-oxo-1,2-dihydroquinolin-3-yl)phosphonate (16d). Colourless oil (1.30 g, 70%). Chromatography (CH₂Cl₂/EtOAc 8/1). Rf: 0.5 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2981, 2931, 2905, 1641, 1563, 1450, 1241, 1223, 1049, 1020, 959. ³¹P NMR (101 MHz, CDCl₃) δ 14.18 ppm. ¹H NMR (250 MHz, CDCl₃) δ 8.53 (d, J = 17.5 Hz, 1H), 7.65 (dd, J = 7.7, 1.5 Hz, 1H), 7.55–7.47 (m, 1H), 7.35–7.17 (m, 7H), 5.55 (s, 2H), 4.44–4.19 (m, 4H), 1.38 (t, J = 7.1 Hz, 6H). ¹³C NMR (63 MHz, CDCl₃) δ 159.71 (d, J = 12.3 Hz), 148.28, 140.28, 135.38, 132.45, 129.82, 128.13, 126.74, 126.08, 122.04, 120.90 (d, J = 196.3 Hz), 118.81 (d, J = 16.5 Hz), 114.50, 62.42 (d, J = 5.9 Hz), 45.23, 15.93 (d, J = 6.0 Hz). ESI-MS [M + H]⁺ = 372. Anal. calcd for C₂₀H₂₂NO₄P: C, 64.68; H, 5.97; N, 4.15. Found: C, 64.58; H, 5.99; N, 4.13%.

Diethyl (2-benzyloxyquiolin-3-yl)phosphonate (17d). Colourless oil (0.186 g, 10%). Chromatography (CH₂Cl₂/EtOAc 8/1). Rf: 0.7 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 3033, 2981, 2930, 2905, 1617, 1592, 1411, 1341, 1249, 1075, 1018, 964. ³¹P NMR (101 MHz, CDCl₃) δ 15.05 ppm. ¹H NMR (250 MHz, CDCl₃) δ 8.59 (dd, J = 16.2, 0.7 Hz, 1H), 7.75 (dd, J = 8.5, 1.1 Hz, 1H), 7.69 (dd, J = 8.1, 1.4 Hz, 1H), 7.60 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.50–7.44 (m, 2H), 7.35–7.14 (m, 4H), 5.53 (s, 2H), 4.17–3.87 (m, 4H), 1.16 (td, J = 7.0, 0.6 Hz, 6H). ¹³C NMR (63 MHz, CDCl₃) δ 160.26 (d, J = 5.0 Hz), 148.22, 147.73 (d, J = 7.2 Hz), 137.03, 131.92, 128.60, 128.31, 127.80, 127.70, 127.09, 124.81, 124.06 (d, J = 12.4 Hz), 113.33 (d, J = 190.3 Hz), 67.91, 62.62 (d, J = 5.8 Hz), 16.33 (d, J = 6.6 Hz). ESI-MS [M + H]⁺ = 372. Anal. calcd for C₂₀H₂₂NO₄P: C, 64.68; H, 5.97; N, 3.77. Found: C, 64.54; H, 5.98; N, 3.85%.

General procedure for the synthesis of 1,4-alkyl or aryl 3-diethoxyphosphorylquinolin-2-ones 18a-o

To a solution of 1-alkyl-3-diethoxyphosphorylquinolin-2-one 16 (1.0 mmol) in THF (5 mL) under argon atmosphere Grignard reagent (3.0 mmol as 2.0 M THF solution) was added dropwise at rt. The reaction mixture was stirred at ambient temperature overnight. Next the saturated ammonium chloride solution in water (10 mL) was added to the reaction mixture and it was extracted with ethyl acetate (2 × 10 mL). Combined organic layers were washed with brine, dried over MgSO₄ and evaporated under reduced pressure, affording the crude product which was purified by column chromatography (eluent CH₂Cl₂/EtOAc). For 1,4-alkyl or aryl 3-diethoxyphosphorylquinolin-2-ones 18b,f,I,m also dephosphorylated side products 19b,f,I,m were isolated and characterized.

Diethyl (4-ethyl-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18a). Light yellow oil (237 mg, 73%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2967, 2930, 1664, 1601, 1472, 1367, 1245, 1017, 962. ³¹P NMR (101 MHz, CDCl₃) δ 22.64 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.25 (ddd, J = 8.0, 7.5, 1.8 Hz, 1H), 7.17 (dd, J = 7.4, 1.7 Hz, 1H), 7.03 (ddd, J = 7.5, 7.4, 1.1 Hz 1H), 6.97 (dd, J = 8.1, 1.1 Hz, 1H), 4.08 (dq, J = 8.0, 7.1 Hz, 2H), 3.72 (m, 1H), 3.47–3.34 (m, 4H), 3.31–3.12 (m, 2H), 1.57 (p, J = 7.4 Hz, 2H), 1.29 (td, J = 7.1, 0.6 Hz, 3H), 0.96–0.79 (m, 6H). ¹³C NMR (63 MHz, CDCl₃) ¹³C NMR (63 MHz, CDCl₃) δ 164.06 (d, J = 5.1 Hz), 138.75, 128.35, 127.25, 126.51, 122.47, 114.24, 61.98 (d, J = 6.6 Hz), 61.65 (d, J = 6.8 Hz), 46.56 (d, J = 127.8 Hz), 38.94 (d, J = 4.3 Hz), 29.29, 28.24 (d, J = 19.3 Hz), 15.72 (d, J = 6.2 Hz), 15.45 (d, J = 6.2 Hz), 10.80. ESI-MS [M + H]⁺ = 326, [M + Na]⁺ = 348. Anal. calcd for C₁₆H₂₄NO₄P: C, 59.07; H, 7.44; N, 4.31. Found: C, 59.19; H, 7.46; N, 4.29%.

Diethyl (1-methyl-2-oxo-4-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18b). Light yellow oil (146 mg, 43%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2962, 2932, 2907, 2873, 1664, 1600, 1498, 1363, 1247, 1017, 965. ³¹P NMR (101 MHz, CDCl₃) δ 23.28 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.26 (ddd, J = 8.1, 7.5, 1.7 Hz, 1H), 7.17 (dd, J = 7.4, 1.7 Hz, 1H), 7.03 (ddd, J = 7.5, 7.4, 1.2 Hz, 1H), 6.97 (dd, J = 8.1, 1.1 Hz, 1H), 4.07 (dq, J = 8.0, 7.1 Hz, 2H), 3.72 (m, 1H), 3.49–3.27 (m, 5H), 3.03 (dd, J = 14.9, 7.3 Hz, 1H), 1.79 (sp, J = 6.9 Hz, 1H), 1.28 (td, J = 7.1, 0.6 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.83 (td, J = 7.1, 0.6 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) ¹³C NMR (63 MHz, CDCl₃) δ 164.87 (d, J = 5.2 Hz), 139.66, 129.68, 127.59, 125.86, 122.64, 114.44, 62.35 (d, J = 6.7 Hz), 62.04 (d, J = 6.8 Hz), 45.84, 43.86 (d, J = 5.3 Hz), 32.76 (d, J = 17.7 Hz), 29.64, 19.80, 19.38, 16.05 (d, J = 6.2 Hz), 15.80 (d, J = 6.2 Hz). ESI-MS [M + H]⁺ = 340. Anal. calcd for C₁₇H₂₆NO₄P: C, 60.17; H, 7.72; N, 4.13. Found: C, 60.03; H, 7.75; N, 4.14%.

1-Methyl-4-(propan-2-yl)-1,2-dihydroquinolin-2-one (19b). Yellow solid (42 mg, 21%) mp 38–39 °C. Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 3036, 2959, 2870, 1639, 1594, 1459, 1226, 1040. ¹H NMR (250 MHz, CDCl₃) δ 7.57–7.46 (m, 3H), 7.33 (dd, J = 8.4, 1.0 Hz, 1H), 7.21 (ddd, J = 7.5, 7.4, 1.0 Hz, 1H), 3.75 (s, 3H), 3.31 (spd, J = 6.9, 0.9 Hz, 1H), 1.27 (s, 3H), 1.25 (s, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 162.11, 139.79, 138.70, 132.24, 129.31, 128.16, 121.88, 120.73, 113.73, 29.71, 28.21, 21.86. ESI-MS [M + H]⁺ = 202. Anal. calcd for C₁₃H₁₅NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.68; H, 7.53; N, 6.94%.

Diethyl (1-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18c). Light yellow oil (280 mg, 75%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.7 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2979, 1665, 1600, 1496, 1471, 1364, 1246, 1014, 965. ³¹P NMR (101 MHz, CDCl₃) δ 21.99 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.40–7.13 (m, 6H), 7.15–6.98 (m, 4H), 4.70 (d, J = 14.6 Hz, 1H), 4.23–4.03 (m, 2H), 3.80 (m, 1H), 3.57–3.44 (m, 1H), 3.55 (dd, J = 25.3, 1.2 Hz, 1H), 3.41 (s, 3H), 1.31 (td, J = 7.1, 0.6 Hz, 3H), 0.93 (td, J = 7.1, 0.6 Hz, 3H). ¹³C NMR (176 MHz, CDCl₃) δ 163.65 (d, J = 5.0 Hz), 141.50 (d, J = 18.8 Hz), 139.76, 128.91, 128.54, 128.03, 126.77, 126.35, 125.22, 123.24, 114.59, 62.41 (d, J = 6.5 Hz), 62.09 (d, J = 5.7 Hz), 48.94 (d, J = 125.2 Hz), 42.24, 29.59 (d, J = 3.2 Hz), 15.88 (d, J = 6.2 Hz), 15.65 (d, J = 6.3 Hz). ESI-MS [M + H]⁺ = 374, [M − H]⁻ = 372. Anal. calcd for C₂₀H₂₄NO₄P: C, 64.34; H, 6.48; N, 3.75. Found: C, 64.25; H, 6.51; N, 3.76%.

Diethyl (1-ethyl-4-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18d). Light yellow oil (182 mg, 56%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2977, 2930, 2870, 1662, 1600, 1496, 1462, 1379, 1248, 1019, 963. ³¹P NMR (101 MHz, CDCl₃) δ 22.49 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.25–7.18 (m, 2H), 7.05–6.97 (m, 2H), 4.23–3.87 (m, 4H), 3.73 (m, 1H), 3.55–3.32 (m, 2H), 3.13 (dd, J = 24.8, 1.2 Hz, 1H), 1.33–1.21 (m, 9H), 0.86 (td, J = 7.1, 0.6 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 163.74 (d, J = 5.5 Hz), 137.67, 128.86, 128.02, 127.60, 123.19, 114.47, 62.51 (d, J = 6.6 Hz), 62.10 (d, J = 6.8 Hz), 48.55 (d, J = 127.5 Hz), 37.42, 32.91 (d, J = 4.2 Hz), 22.39 (d, J = 20.6 Hz), 16.12 (d, J = 6.2 Hz), 15.81 (d, J = 6.4 Hz), 12.25. ESI-MS [M + H]⁺ = 326, [M + Na]⁺ = 348. Anal. calcd for C₁₆H₂₄NO₄P: C, 59.07; H, 7.44; N, 4.31. Found: C, 58.90; H, 7.48; N, 4.31%.

Diethyl (1,4-diethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18e). Light yellow oil (299 mg, 88%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2973, 2932, 2874, 1663, 1600, 1495, 1460, 1377, 1244, 1018, 962. ³¹P NMR (101 MHz, CDCl₃) δ 22.80 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.25 (ddd, J = 8.7, 7.5, 1.7 Hz, 1H), 7.17 (dd, J = 7.7, 1.7 Hz, 1H), 7.04–6.98 (m, 2H), 4.16–3.86 (m, 4H), 3.80–3.56 (m, 1H), 3.47–3.31 (m, 1H), 3.23 (dd, J = 25.4, 1.1 Hz, 1H), 3.22–3.10 (m, 1H), 1.56 (p, J = 7.4 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 163.59 (d, J = 5.4 Hz), 137.64, 128.79, 127.35, 126.85, 122.41, 114.14, 62.10 (d, J = 6.7 Hz), 61.71 (d, J = 6.7 Hz), 46.69 (d, J = 127.8 Hz), 39.12 (d, J = 4.4 Hz), 37.04, 28.30 (d, J = 19.5 Hz), 15.81 (d, J = 6.3 Hz), 15.51 (d, J = 6.3 Hz), 11.89, 10.88. ESI-MS [M + H]⁺ = 340, [M + Na]⁺ = 362. Anal. calcd for C₁₇H₂₆NO₄P: C, 60.17; H, 7.72; N, 4.13. Found: C, 60.06; H, 7.77; N, 4.14%.

Diethyl [1-ethyl-2-oxo-4-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-3-yl]phosphonate (18f). Light yellow oil (177 mg, 50%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2972, 2933, 1662, 1600, 1496, 1460, 1381, 1247, 1019, 965. ³¹P NMR (101 MHz, CDCl₃) δ 23.47 ppm. ¹H NMR (250 MHz, CHCl₃) δ 7.25 (ddd, J = 8.1, 7.5, 1.9 Hz, 1H), 7.17 (dd, J = 8.2, 1.9 Hz, 1H), 7.04–6.98 (m, 2H), 4.19–3.87 (m, 4H), 3.80–3.65 (m, 1H), 3.49–3.37 (m, 1H), 3.37 (dd, J = 26.2, 1.0 Hz, 1H), 3.02 (ddd, J = 15.2, 7.2, 1.0 Hz, 1H), 1.77 (p, J = 7.2 Hz, 1H), 1.28 (td, J = 7.0, 0.6 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.89 (td, J = 7.0, 0.6 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 164.55 (d, J = 5.4 Hz), 138.71, 130.32, 127.81, 126.36, 122.70, 114.49, 62.67 (d, J = 6.7 Hz), 62.30 (d, J = 6.9 Hz), 44.66 (d, J = 128.0 Hz), 44.21 (d, J = 4.4 Hz), 37.46, 33.12 (d, J = 18.0 Hz), 20.11, 19.65, 16.30 (d, J = 6.2 Hz), 16.01 (d, J = 6.3 Hz), 12.30. ESI-MS [M + H]⁺ = 354. Anal. calcd for C₁₈H₂₈NO₄P: C, 61.18; H, 7.99; N, 3.96. Found: C, 61.05; H, 8.03; N, 3.94%.

1-Ethyl-4-(propan-2-yl)-1,2-dihydroquinolin-2-one (19f). Colourless oil (82 mg, 38%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2960, 2932, 2870, 1638, 1595, 1580, 1456, 1069. ¹H NMR (250 MHz, CDCl₃) δ 7.55–7.44 (m, 3H), 7.36–7.31 (dd, J = 8.4, 1.1 Hz, 1H), 7.18 (ddd, J = 7.7, 7.2, 1.1 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.31 (spd, J = 6.9, 1.1 Hz, 1H), 1.35 (t, J = 7.1 Hz, 3H), 1.26 (s, 3H), 1.23 (s, 3H). ¹³C NMR (176 MHz, CDCl₃) δ 161.62, 139.95, 137.78, 132.28, 129.33, 128.49, 121.70, 121.13, 113.68, 37.67, 28.10, 21.96, 12.83. ESI-MS [M + H]⁺ = 216. Anal. calcd for C₁₄H₁₇NO: C, 78.10; H, 7.96; N, 6.51. Found: C, 78.18; H, 7.98; N, 6.46%.

Diethyl (1-ethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18g). Light yellow oil (248 mg, 64%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2978, 2934, 2908, 1664, 1601, 1462, 1380, 1246, 1016, 964. ³¹P NMR (101 MHz, CDCl₃) δ 22.02 ppm. ¹H NMR (700 MHz, CDCl₃) δ 7.31 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 7.28 (dd, J = 7.5, 1.6 Hz, 1H), 7.24–7.20 (m, 2H), 7.19–7.14 (m, 1H), 7.09 (dd, J = 8.3, 1.0 Hz, 1H), 7.08–7.01 (m, 3H), 4.68 (d, J = 14.7 Hz, 1H), 4.18–4.04 (m, 3H), 4.00 (dq, J = 14.2, 7.1 Hz, 1H), 3.84–3.78 (m, 1H), 3.55–3.49 (m, 1H), 3.51 (dd, J = 25.0, 1.1 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H). ¹³C NMR (176 MHz, CDCl₃) δ 163.55 (d, J = 5.1 Hz), 141.88 (d, J = 19.0 Hz), 139.03, 129.79, 128.85, 128.36, 127.13, 126.90, 125.85, 123.48, 114.74, 62.88 (d, J = 6.7 Hz), 62.44 (d, J = 6.8 Hz), 49.38 (d, J = 124.9 Hz), 42.69 (d, J = 3.5 Hz), 37.53, 16.27 (d, J = 6.3 Hz), 15.99 (d, J = 6.3 Hz), 12.28. ESI-MS [M + H]⁺ = 388, [M + Na]⁺ = 410. Anal. calcd for C₂₁H₂₆NO₄P: C, 65.11; H, 6.76; N, 3.62. Found: C, 65.02; H, 6.78; N, 3.59%.

Diethyl (1-butyl-4-ethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18h). Light yellow oil (312 mg, 85%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.7 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2960, 2931, 2873, 1663, 1600, 1460, 1378, 1247, 1020, 963. ³¹P NMR (101 MHz, CDCl₃) δ 22.68 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.23 (ddd, J = 8.0, 7.7, 1.7 Hz, 1H), 7.16 (dd, J = 7.5, 1.7 Hz, 1H), 7.00 (ddd, J = 7.7, 7.5, 1.1 Hz, 1H), 6.97 (dd, J = 8.0, 1.1 Hz, 1H), 4.07 (dq, J = 8.1, 7.1 Hz, 2H), 3.93 (t, J = 7.7 Hz, 2H), 3.79–3.64 (m, 1H), 3.37 (qdd, J = 10.0, 8.6, 7.0 Hz, 1H), 3.22 (dd, J = 25.2, 1.1 Hz, 2H), 1.72–1.46 (m, 4H), 1.45–1.28 (m, 2H), 1.28 (td, J = 7.0, 0.5 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H), 0.89 (d, J = 7.6 Hz, 3H), 0.85 (td, J = 7.1, 0.5 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 163.85 (d, J = 5.3 Hz), 137.89, 128.84, 127.34, 126.92, 122.43, 114.33, 62.13 (d, J = 6.4 Hz), 61.74 (d, J = 6.9 Hz), 46.76 (d, J = 127.9 Hz), 41.83, 39.21 (d, J = 4.4 Hz), 28.66, 28.43 (d, J = 19.7 Hz), 19.80, 15.85 (d, J = 6.2 Hz), 15.56 (d, J = 6.3 Hz), 13.42, 10.96. ESI-MS [M + H]⁺ = 368, [M − H]⁻ = 366. Anal. calcd for C₁₉H₃₀NO₄P: C, 62.11; H, 8.23; N, 3.81. Found: C, 62.25; H, 8.25; N, 3.77%.

Diethyl [1-butyl-2-oxo-4-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-3-yl]phosphonate (18i). Light yellow oil (156 mg, 41%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2958, 2932, 2872, 1662, 1600, 1460, 1382, 1249, 1020, 962. ³¹P NMR (101 MHz, CDCl₃) δ 23.32 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.23 (ddd, J = 8.2, 7.3, 1.6 Hz, 1H), 7.15 (dd, J = 7.4, 1.6 Hz, 1H), 7.00 (ddd, J = 7.4, 7.3, 1.0 Hz, 1H), 6.96 (dd, J = 8.2, 1.0 Hz, 1H), 4.12–4.00 (m, 2H), 3.91 (t, J = 7.8 Hz, 2H), 3.83–3.60 (m, 1H), 3.45–3.32 (m, 1H), 3.35 (dd, J = 26.1, 1.1 Hz, 1H), 3.00 (dd, J = 15.1, 7.3 Hz, 1H), 1.85–1.70 (m, 1H), 1.69–1.49 (m, 2H), 1.48–1.30 (m, 2H), 1.27 (td, J = 7.1, 0.6 Hz, 3H), 0.98–0.81 (m, 12H). ¹³C NMR (63 MHz, CDCl₃) δ 164.54 (d, J = 5.4 Hz), 138.82, 130.15, 127.64, 126.23, 122.52, 114.48, 62.49 (d, J = 6.7 Hz), 62.13 (d, J = 7.0 Hz), 46.02, 44.16 (d, J = 4.4 Hz), 43.99, 42.25, 32.88 (d, J = 17.8 Hz), 28.90, 20.10 (d, J = 8.5 Hz), 19.54, 16.15 (d, J = 6.2 Hz), 15.88 (d, J = 6.2 Hz), 13.72. ESI-MS [M + H]⁺ = 382. Anal. calcd for C₂₀H₃₂NO₄P: C, 62.97; H, 8.46; N, 3.65. Found: C, 63.11; H, 8.48; N, 3.66%.

1-Butyl-4-(propan-2-yl)-1,2-dihydroquinolin-2-one (19i). Yellow oil (114 mg, 47%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2957, 2930, 2869, 1640, 1625, 1595, 1455, 1207. ¹H NMR (250 MHz, CDCl₃) δ 7.56–7.44 (m, 3H), 7.32 (dd, J = 8.1, 1.1 Hz, 1H), 7.19 (ddd, J = 7.7, 7.2, 1.1 Hz, 1H), 4.35–4.26 (m, 2H), 3.31 (spd, J = 6.8, 0.9 Hz, 1H), 1.81–1.64 (m, 2H), 1.58–1.40 (m, 2H), 1.27 (s, 3H), 1.25–1.17 (m, 2H), 1.24 (s, 3H), 1.00 (t, J = 7.3 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 161.72, 139.73, 137.90, 132.16, 129.17, 128.35, 121.58, 120.97, 113.71, 42.46, 29.59, 28.07, 21.83, 20.34, 13.84. ESI-MS [M + H]⁺ = 244. Anal. calcd for C₁₆H₂₁NO: C, 78.97; H, 8.70; N, 5.76. Found: C, 79.09; H, 8.75; N, 5.77%.

Diethyl (1-butyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18j). Light yellow oil (378 mg, 91%). Chromatography (CH₂Cl₂ : EtOAc = 6 : 1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 2958, 2931, 2871, 1663, 1600, 1461, 1372, 1245, 1049, 1016. ³¹P NMR (101 MHz, CDCl₃) δ 22.09 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.36–7.15 (m, 5H), 7.10–7.00 (m, 4H), 4.68 (d, J = 15.1. 1H), 4.20–4.05 (m, 2H), 3.96 (m, 2H), 3.80 (m, 1H), 3.59–4.42 (m, 1H), 3.51 (dd, J = 25.2, 1.2 Hz, 2H), 1.72–1.49 (m, 2H), 1.42–1.25 (m, 2H), 1.31 (td, J = 7.1, 0.6 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H), 0.92 (td, J = 7.1, 0.6 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 163.58 (d, J = 5.1 Hz), 141.68 (d, J = 19.1 Hz), 139.07, 129.62, 128.67, 128.23, 126.98, 126.75, 125.65, 123.31, 114.77, 62.72 (d, J = 6.5 Hz), 62.33 (d, J = 6.9 Hz), 49.20 (d, J = 125.3 Hz), 42.48 (d, J = 3.5 Hz), 42.17, 28.88, 20.04, 16.12 (d, J = 6.3 Hz), 15.86 (d, J = 6.4 Hz), 13.66. ESI-MS [M + H]⁺ = 416, [M + Na]⁺ = 438. Anal. calcd for C₂₃H₃₀NO₄P: C, 66.49; H, 7.28; N, 3.37. Found: C, 66.35; H, 7.31; N, 3.36%.

Diethyl (1-benzyl-4-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18k). Light yellow oil (209 mg, 54%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2980, 2928, 1664, 1601, 1496, 1378, 1251, 1052, 1019, 961. ³¹P NMR (101 MHz, CDCl₃) δ 22.28 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.34–7.23 (m, 5H), 7.20 (dd, J = 7.4, 1.8 Hz, 1H), 7.10 (ddd, J = 8.1, 7.5, 1.8 Hz, 1H), 6.99 (ddd, J = 7.5, 7.4, 1.2 Hz, 1H), 6.84 (dd, J = 8.1, 1.2 Hz, 1H), 5.62 (d, J = 16.3 Hz, 1H), 4.80 (d, J = 16.3 Hz, 1H), 4.13 (dq, J = 8.1, 7.1 Hz, 2H), 3.89–3.71 (m, 1H), 3.56 (m, 1H), 3.46–3.34 (m, 1H), 3.27 (dd, J = 25.1, 1.1 Hz, 1H), 1.34–1.27 (m, 6H), 0.83 (td, J = 7.1, 0.6 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 163.58 (d, J = 5.0 Hz), 137.48, 135.88, 127.78, 127.56, 126.79, 126.61, 126.04, 125.39, 122.51, 114.59, 61.67 (d, J = 6.4 Hz), 61.31 (d, J = 6.9 Hz), 47.70 (d, J = 127.6 Hz), 45.86, 32.02 (d, J = 4.4 Hz), 21.77 (d, J = 20.2 Hz), 15.22 (d, J = 6.2 Hz), 14.85 (d, J = 6.3 Hz). ESI-MS [M + H]⁺ = 388, [M − H]⁻ = 386. Anal. calcd for C₂₁H₂₆NO₄P: C, 65.11; H, 6.76; N, 3.62. Found: C, 64.99; H, 6.79; N, 3.60%.

Diethyl (1-benzyl-4-ethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18l). Light yellow solid (261 mg, 65%) mp 84–85 °C. Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2962, 2932, 1664, 1602, 1495, 1458, 1382, 1242, 1181, 1017, 955. ³¹P NMR (101 MHz, CDCl₃) δ 22.72 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.32–7.23 (m, 5H), 7.18 (dd, J = 7.4, 1.8 Hz, 1H), 7.10 (ddd, J = 8.1, 7.5, 1.8 Hz, 1H), 6.99 (ddd, J = 7.5, 7.4, 1.2 Hz, 1H), 6.83 (dd, J = 8.1, 1.2 Hz, 1H), 5.62 (d, J = 16.3 Hz, 1H), 4.74 (d, J = 16.3 Hz, 1H), 4.23–4.03 (m, 2H), 3.79 (m, 1H), 3.44–3.19 (m, 3H), 1.63 (p, J = 7.6 Hz, 2H), 1.31 (td, J = 7.1, 0.5 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H), 0.83 (td, J = 7.1, 0.6 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 164.79, 138.76, 136.87, 128.87, 128.52, 127.62, 127.09, 126.98, 126.30, 123.05, 115.55, 62.59 (d, J = 6.4 Hz), 62.24 (d, J = 6.8 Hz), 47.05 (d, J = 128.7 Hz), 46.89, 39.50 (d, J = 4.2 Hz), 28.90 (d, J = 19.4 Hz), 16.20 (d, J = 6.2 Hz), 15.84 (d, J = 6.3 Hz), 11.32. ESI-MS [M + H]⁺ = 402, [M + Na]⁺ = 324. Anal. calcd for C₂₂H₂₈NO₄P: C, 65.82; H, 7.03; N, 3.49. Found: C, 65.96; H, 7.01; N, 3.52%.

Diethyl [1-benzyl-2-oxo-4-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-3-yl]phosphonate (18m). White solid (241 mg, 58%) mp 85–87. Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2996, 2966, 2931, 2876, 1664, 1601, 1457, 1369, 1241, 1049, 1020, 967. ³¹P NMR (101 MHz, CDCl₃) δ 23.37 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.33–7.22 (m, 5H), 7.17 (dd, J = 7.4, 1.7 Hz, 1H), 7.09 (ddd, J = 8.0, 7.5, 1.7 Hz, 1H), 6.98 (dd, J = 7.5, 7.4, 1.2 Hz, 1H), 6.83 (dd, J = 8.0, 1.2 Hz, 1H), 5.64 (d, J = 16.3 Hz, 1H), 4.66 (d, J = 16.3 Hz, 1H), 4.21–4.05 (m, 2H), 3.89–3.71 (m, 1H), 3.49 (dd, J = 26.5, 1.1 Hz, 1H), 3.34 (m, 1H), 3.11 (dd, J = 15.0, 7.2 Hz, 1H), 1.85 (sp, J = 6.8 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H), 0.87–0.82 (m, 6H). ¹³C NMR (176 MHz, CHCl₃) δ 165.25 (d, J = 5.4 Hz), 139.56, 137.02, 129.90, 128.57, 127.71, 127.04, 126.43, 126.17, 122.91, 115.52, 62.66 (d, J = 6.7 Hz), 62.35 (d, J = 6.6 Hz), 47.12, 45.20 (d, J = 127.8 Hz), 44.22 (d, J = 4.3 Hz), 33.12 (d, J = 17.7 Hz), 20.07, 19.68, 16.26 (d, J = 6.2 Hz), 15.92 (d, J = 6.2 Hz). ESI-MS [M + H]⁺ = 416, [M − H]⁻ = 414. Anal. calcd for C₂₃H₃₀NO₄P: C, 66.49; H, 7.28; N, 3.37. Found: C, 66.70; H, 7.31; N, 3.37%.

1-Benzyl-4-(propan-2-yl)-1,2-dihydroquinolin-2-one (19m). Yellow oil (53 mg, 19%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 3061, 3031, 2959, 2870, 1640, 1593, 1495, 1453, 1226, 1207, 1069, 971. ¹H NMR (700 MHz, CDCl₃) δ 7.60 (s, 1H), 7.58 (dd, J = 7.7, 1.5 Hz, 1H), 7.39 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.34–7.30 (m, 2H), 7.28–7.24 (m, 4H), 7.19 (ddd, J = 8.0, 7.3, 1.0 Hz, 1H), 5.62 (s, 2H), 3.42 (spd, J = 6.9, 0.9 Hz, 1H), 1.35 (s, 3H), 1.34 (s, 3H). ¹³C NMR (176 MHz, CDCl₃) δ 162.34, 139.98, 138.34, 136.83, 132.87, 129.42, 128.83, 128.37, 127.24, 126.76, 122.07, 121.12, 114.72, 46.40, 28.30, 22.02. ESI-MS [M + H]⁺ = 278. Anal. calcd for C₁₉H₁₉NO: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.40; H, 6.92; N, 5.06%.

Diethyl (1-benzyl-4-ethenyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18n). Light yellow solid (84 mg, 21%) mp 69–71 °C. Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.6 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2980, 1666, 1601, 1495, 1461, 1378, 1250, 1172, 1049, 1017, 966. ³¹P NMR (101 MHz, CDCl₃) δ 22.07 ppm. ¹H NMR (250 MHz, CHCl₃) δ 7.31–7.20 (m, 5H), 7.21 (dd, J = 7.4, 1.8 Hz, 1H), 7.12 (ddd, J = 8.1, 7.6, 1.8 Hz, 1H), 7.01 (ddd, J = 7.6, 7.4, 1.2 Hz, 1H), 6.86 (dd, J = 8.1, 1.2 Hz, 1H), 5.91 (ddd, J = 17.1, 10.2, 5.6 Hz, 1H), 5.50 (d, J = 16.3 Hz, 1H), 5.08 (ddd, J = 10.2, 1.6, 0.8 Hz, 1H), 4.88 (ddd, J = 17.0, 1.8, 0.9 Hz, 2H), 4.82 (d, J = 16.4 Hz, 0H), 4.21–4.08 (m, 3H), 3.81 (m, 1H), 3.46 (dd, J = 25.0, 1.4 Hz, 1H), 3.48–3.34 (m, 1H), 1.32 (td, J = 7.1, 0.6 Hz, 3H), 0.86 (td, J = 7.1, 0.6 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 164.38 (d, J = 5.3 Hz), 139.02, 137.94 (d, J = 20.6 Hz), 136.71, 128.75, 128.47, 128.03, 126.99, 126.38, 125.00, 123.48, 115.83, 115.64, 62.79 (d, J = 6.4 Hz), 62.39 (d, J = 6.7 Hz), 47.57 (d, J = 128.0 Hz), 46.56, 41.09 (d, J = 3.1 Hz), 16.19 (d, J = 6.1 Hz), 15.83 (d, J = 6.3 Hz). ESI-MS [M + H]⁺ = 400, [M − H]⁻ = 398. Anal. calcd for C₂₂H₂₆NO₄P: C, 59.07; H, 7.44; N, 4.31. Found: C, 59.15; H, 7.49; N, 4.29%.

Diethyl (1-benzyl-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)phosphonate (18o). Light yellow oil (355 mg, 79%). Chromatography (CH₂Cl₂/EtOAc 6/1). Rf: 0.7 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 3062, 3029, 2981, 2931, 2907, 1666, 1601, 1495, 1462, 1379, 1248, 1167, 1017, 965. ³¹P NMR (101 MHz, CDCl₃) δ 21.53 ppm. ¹H NMR (250 MHz, CDCl₃) δ 7.35–7.26 (m, 8H), 7.25–7.20 (m, 2H), 7.12–7.04 (m, 3H), 7.04–6.99 (m, 1H), 5.55 (d, J = 16.2 Hz, 1H), 4.96 (d, J = 16.2 Hz, 1H), 4.82 (d, J = 14.7 Hz, 1H), 4.33–4.12 (m, 2H), 3.93 (m, 1H), 3.72 (dd, J = 25.3, 1.1 Hz, 1H), 3.64–3.45 (m, 1H), 1.38 (td, J = 7.1, 0.6 Hz, 3H), 0.95 (td, J = 7.1, 0.6 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 164.42 (d, J = 4.1 Hz), 141.89, 141.59, 139.71, 136.78, 129.50, 128.97, 128.63, 128.36, 127.24, 127.04, 126.76, 125.80, 123.81, 115.87, 62.97 (d, J = 6.7 Hz), 62.70 (d, J = 6.8 Hz), 49.44 (d, J = 125.5 Hz), 46.90, 42.65, 16.35 (d, J = 7.5 Hz), 15.97 (d, J = 7.5 Hz). ESI-MS [M + H]⁺ = 450, [M − H]⁻ = 448. Anal. calcd for C₂₆H₂₈NO₄P: C, 69.48; H, 6.28; N, 3.12. Found: C, 69.67; H, 6.31; N, 3.12%.

General procedure for the synthesis of 1,4-alkil or aryl 3-methylidene-1,2,3,4-tetrahydroquinolin-2-ones 20a-m,o

To the solution of 1,4-alkyl or aryl 3-diethoxyphosphorylquinolin-2-one 18 (0.5 mmol) in THF (2 mL) under argon atmosphere, sodium hydride (16.5 mg, 0.55 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 5 min. Then formaldehyde (75.1 mg, 2.5 mmol) was added. After 4 hours water was added (3 mL) and the mixture was extracted with dichloromethane (2 × 5 mL) Combined organic layers were washed with brine, dried over MgSO₄ and evaporated under reduced pressure, affording the crude product which was purified by column chromatography (CH₂Cl₂).

4-Ethyl-1-Methyl-3-methylidene-1,2,3,4-tetrahydroquinolin-2-one (20a). Colourless oil (82 mg, 82%). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 2963, 2930, 2873, 1666, 1628, 1597, 1497, 1459, 1351, 1112, 1050. ¹H NMR (250 MHz, CDCl₃) δ 7.29–7.22 (m, 1H), 7.14 (dd, J = 7.3, 1.6 Hz, 1H), 7.03 (ddd, J = 7.4, 7.3, 1.1 Hz, 1H), 6.98 (dd, J = 8.1, 1.1 Hz, 1H), 6.17 (d, J = 1.6 Hz, 1H), 5.43 (dd, J = 1.6, 0.8 Hz, 1H), 3.40 (s, 3H), 1.71–1.49 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 164.65, 140.22, 138.81, 128.84, 127.92, 127.49, 123.41, 122.90, 114.70, 47.10, 30.03, 29.71, 11.17. ESI-MS [M + H]⁺ = 202. Anal. calcd for C₁₃H₁₅NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.72; H, 7.55; N, 6.96%.

1-Methyl-3-Methylidene-4-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-2-one (20b). White solid (94 mg, 87%) mp 43–44 °C. Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 2977, 2964, 2909, 2867, 1666, 1636, 1596, 1471, 1350, 1120, 1049. ¹H NMR (250 MHz, CDCl₃) δ 7.26 (ddd, J = 8.1, 7.6, 1.7 Hz, 1H), 7.11 (dd, J = 7.5, 1.7 Hz, 1H), 7.02 (ddd, J = 7.6, 7.3, 1.2 Hz, 1H), 6.96 (dd, J = 8.1, 1.2 Hz, 1H), 6.17 (d, J = 1.7 Hz, 1H), 5.38 (dd, J = 1.7, 0.8 Hz, 1H), 3.37 (s, 3H), 3.19 (d, J = 7.3 Hz, 1H), 1.79 (dqd, J = 6.9, 6.8 Hz, 1H), 0.86 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 165.30, 139.50, 139.38, 128.99, 127.86, 127.58, 124.28, 122.62, 114.66, 52.28, 33.64, 29.74, 20.31, 19.34. ESI-MS [M + H]⁺ = 216. Anal. calcd for C₁₄H₁₇NO: C, 78.10; H, 7.96; N, 6.51. Found: C, 78.22; H, 7.94; N, 6.55%.

1-Methyl-3-Methylidene-4-phenyl-1,2,3,4-tetrahydroquinolin-2-one (20c)¹⁶. White solid (112 mg, 90%) mp 38–39 °C. Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 3052, 3021, 2922, 2849, 1671, 1633, 1597, 1454, 1352, 1110, 945. ¹H NMR (700 MHz, CDCl₃) δ 7.35 (ddd, J = 7.8, 7.6, 1.6 Hz, 1H), 7.32–7.29 (m, 2H), 7.26–7.24 (m, 1H), 7.19 (dd, J = 7.6, 1.1 Hz, 1H), 7.17–7.13 (m, 2H), 7.11–7.05 (m, 2H), 6.31 (t, J = 1.1 Hz, 1H), 5.57 (d, J = 1.3 Hz, 1H), 4.91 (s, 1H), 3.43 (s, 3H). ¹³C NMR (176 MHz, CDCl₃) δ 164.40, 140.90, 140.34, 139.58, 128.77, 128.75, 128.14, 127.67, 127.14, 127.10, 124.20, 123.14, 114.93, 49.48, 29.91. ESI-MS [M + H]⁺ = 250.2. Anal. calcd for C₁₇H₁₅NO: C, 81.83; H, 6.06; N, 5.62. Found: C, 81.99; H, 6.08; N, 5.59%.

1-Ethyl-4-Methyl-3-methylidene-1,2,3,4-tetrahydroquinolin-2-one (20d). White solid (80 mg, 80%) mp 84–85 °C. Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 2958, 1664, 1624, 1575, 1368, 1258, 1127. ¹H NMR (700 MHz, CDCl₃) δ 7.23 (ddd, J = 8.0, 7.6, 1.8 Hz, 1H), 7.17 (ddd, J = 7.6, 1.6, 0.8 Hz, 1H), 7.02 (m, 2H), 6.09 (m, 1H), 5.44 (dd, J = 1.3 Hz, 1.4 Hz, 1H), 4.09 (m, 1H), 4.02 (m, 1H), 3.71–3.67 (m, 1H), 1.34 (d, J = 7.2 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H). ¹³C NMR (176 MHz, CDCl₃) δ 164.12, 142.35, 137.60, 130.13, 127.53, 127.10, 123.05, 121.53, 114.78, 39.26, 37.50, 22.63, 12.64. ESI-MS [M + H]⁺ = 202. Anal. calcd for C₁₃H₁₅NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.70; H, 7.53; N, 6.93%.

1,4-Diethyl-3-methylidene-1,2,3,4-tetrahydroquinolin-2-one (20e). Colourless oil (99 mg, 92%). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2968, 2933, 2874, 1665, 1622, 1590, 1495, 1457, 1371, 1252. ¹H NMR (250 MHz CDCl₃) δ 7.24 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 7.13 (dd, J = 8.1, 1.7 Hz, 1H), 7.05–6.97 (m, 2H), 6.14 (d, J = 1.6 Hz, 1H), 5.40 (dd, J = 1.6, 0.7 Hz, 1H), 4.13–3.95 (m, 2H), 3.45–3.31 (m, 1H), 1.69–1.47 (m, 2H), 1.29 (t, J = 7.1, 3H), 0.88 (t, J = 7.4 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 164.02, 140.53, 137.62, 129.12, 128.26, 127.50, 123.01, 122.75, 114.72, 47.15, 37.30, 30.18, 12.56, 11.08. ESI-MS [M + H]⁺ = 216. Anal. calcd for C₁₄H₁₇NO: C, 78.10; H, 7.96; N, 6.51. Found: C, 78.27; H, 7.98; N, 6.50%.

1-Ethyl-3-Methylidene-4-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-2-one (20f). Colourless oil (102 mg, 89%). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 1 : 1). IR (neat) ν (cm⁻¹): 2959, 2934, 1665, 1630, 1599, 1495, 1461, 1372, 1256, 1123. ¹H NMR (250 MHz, CDCl₃) δ 7.24 (ddd, J = 8.2, 7.6, 1.8 Hz, 1H), 7.11 (dd, J = 8.1, 1.8 Hz, 1H), 7.04–6.96 (m, 2H), 6.16 (d, J = 1.7 Hz, 1H), 5.36 (dd, J = 1.7, 0.8 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 3.20 (d, J = 6.9 Hz, 1H), 1.85–1.70 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 164.64, 139.67, 138.18, 129.31, 128.09, 127.57, 123.95, 122.44, 114.66, 52.19, 37.18, 34.04, 20.18, 19.16, 12.53. ESI-MS [M + H]⁺ = 230. Anal. calcd for C₁₅H₁₉NO: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.71; H, 8.39; N, 6.11%.

1-Ethyl-3-Methylidene-4-phenyl-1,2,3,4-tetrahydroquinolin-2-one (20g). Colourless oil (96 mg, 73%). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 3057, 3026, 2973, 2931, 1665, 1627, 1597, 1493, 1459, 1371, 1256, 1114. ¹H NMR (700 MHz, CDCl₃) δ 7.34 (ddd, J = 8.8, 7.5, 1.6 Hz, 1H), 7.32–7.27 (m, 2H), 7.26–7.21 (m, 1H), 7.21–7.17 (m, 1H), 7.12 (m, 3H), 7.07 (ddd, J = 7.5, 7.4, 1.1 Hz, 1H), 6.26 (t, J = 1.0 Hz, 1H), 5.55 (t, J = 1.3 Hz, 1H), 4.88 (s, 1H), 4.06 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 163.85, 141.07, 140.72, 138.48, 129.14, 128.77, 128.18, 127.67, 127.45, 127.13, 123.76, 123.07, 115.06, 49.67, 37.52, 12.57. ESI-MS [M + H]⁺ = 264. Anal. calcd for C₁₈H₁₇NO: C, 82.10; H, 6.51; N, 5.32. Found: C, 82.01; H, 6.58; N, 5.27%.

1-Butyl-4-ethyl-3-methylidene-1,2,3,4-tetrahydroquinolin-2-one (20h). Colourless oil (112 mg, 92%). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 2959, 2930, 2872, 1666, 1630, 1598, 1495, 1460, 1368, 1119, 935. ¹H NMR (250 MHz, CDCl₃) δ 7.28–7.19 (m, 1H), 7.16–7.10 (m, 1H), 7.05–6.96 (m, 2H), 6.13 (d, J = 1.6 Hz, 1H), 5.40 (dd, J = 1.5, 0.7 Hz, 1H), 4.13–3.82 (m, 2H), 3.38 (dd, J = 8.1, 6.6 Hz, 1H), 1.81–1.50 (m, 4H), 1.50–1.34 (m, 2H), 1.01–0.93 (t, J = 7.4 Hz, 3H), 0.93–0.84 (t, J = 7.4 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 164.24, 140.55, 137.74, 129.13, 128.25, 127.45, 122.96, 122.72, 114.86, 47.20, 41.88, 30.21, 29.16, 20.35, 13.88, 11.12. ESI-MS [M + H]⁺ = 244. Anal. calcd for C₁₆H₂₁NO: C, 78.97; H, 8.74; N, 5.76. Found: C, 79.10; H, 8.70; N, 5.74%.

1-Butyl-3-methylidene-4-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-2-one (20i). Colourless oil (117 g, 91%). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 2957, 2930, 2871, 1666, 1631, 1598, 1494, 1457, 1366, 1205, 1140. ¹H NMR (250 MHz, CDCl₃) δ 7.25 (ddd, J = 8.1, 7.5, 1.8 Hz, 1H), 7.17–7.05 (m, 1H), 7.07–6.92 (m, 2H), 6.15 (d, J = 1.7 Hz, 1H), 5.36 (dd, J = 1.7, 0.8 Hz, 1H), 4.04 (m, 1H), 3.85 (m, 1H), 3.19 (d, J = 7.1 Hz, 1H), 1.85–1.71 (m, 1H), 1.71–1.51 (m, 1H), 1.50–1.34 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 6.9 Hz, 6H). ¹³C NMR (63 MHz, CDCl₃) δ 164.73, 139.68, 138.27, 129.23, 128.00, 127.47, 123.75, 122.33, 114.68, 52.19, 41.88, 33.86, 29.09, 20.38, 20.16, 19.15, 13.85. ESI-MS [M + H]⁺ = 258. Anal. calcd for C₁₇H₂₃NO: C, 79.33; H, 9.01; N, 5.44. Found: C, 79.45; H, 9.07; N, 5.45%.

1-Butyl-3-methylidene-4-phenyl-1,2,3,4-tetrahydroquinolin-2-one (20j). White solid (137 mg, 94%) mp 51–53 °C. Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 2952, 2928, 2868, 1626, 1599, 1456, 1375, 1321, 1112. ¹H NMR (700 MHz, CDCl₃) δ 7.36 (ddd, J = 8.5, 7.5, 1.6 Hz, 1H), 7.32–7.30 (m, 2H), 7.26–7.24 (m, 1H), 7.23–7.22 (dd, J = 7.3, 1.7 Hz, 1H), 7.16–7.14 (m, 2H), 7.12 (dd, J = 8.3, 1.0 Hz, 1H), 7.10 (ddd, J = 7.4, 7.3, 1.1 Hz, 1H), 6.28 (d, J = 1.0 Hz, 1H), 5.58 (d, J = 1.2 Hz, 1H), 4.90 (s, 1H), 4.17–4.12 (m, 1H), 3.93–3.89 (m, 1H), 1.74–1.67 (m, 1H), 1.65–1.58 (m, 1H), 1.39–1.25 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). ¹³C NMR (176 MHz, CDCl₃) δ 164.17, 140.99, 140.76, 138.58, 129.16, 128.71, 128.13, 127.64, 127.54, 127.11, 123.67, 123.02, 115.25, 49.63, 41.90, 29.11, 20.17, 13.87. ESI-MS [M + H]⁺ = 292. Anal. calcd for C₂₀H₂₁NO: C, 82.44; H, 7.26; N, 4.81. Found: C, 82.66; H, 7.30; N, 4.80%.

1-Benzyl-4-Methyl-3-methylidene-1,2,3,4-tetrahydroquinolin-2-one (20k). Colourless oil (124 mg, 94%). Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 3062, 3031, 2963, 2924, 1666, 1630, 1597, 1367, 1318, 1186. ¹H NMR (250 MHz, CDCl₃) δ 7.37–7.16 (m, 6H), 7.11 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H), 7.01 (ddd, J = 7.4, 6.5, 1.3 Hz, 1H), 6.88 (dd, J = 8.0, 1.3 Hz, 1H), 6.22 (d, J = 1.1 Hz, 1H), 5.56 (d, J = 1.3 Hz, 1H), 5.37 (d, J = 16.2 Hz, 1H), 5.19 (d, J = 16.2 Hz, 1H), 3.81 (q, J = 7.3 Hz, 1H), 1.44 (d, J = 7.1 Hz, 2H). ¹³C NMR (63 MHz, CDCl₃) δ 164.83, 141.95, 137.75, 136.80, 129.78, 128.75, 127.41, 127.07, 126.88, 126.44, 123.27, 122.32, 115.70, 46.32, 39.17, 22.74. ESI-MS [M + H]⁺ = 264. Anal. calcd for C₁₈H₁₇NO: C, 82.10; H, 6.51; N, 5.32. Found: C, 82.23; H, 6.52; N, 5.29%.

1-Benzyl-4-Ethyl-3-methylidene-1,2,3,4-tetrahydroquinolin-2-one (20l). White solid (133 mg, 96%) mp 115–117 °C. Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 2963, 2922, 1668, 1634, 1597, 1494, 1451, 1370, 1187, 1017. ¹H NMR (250 MHz, CDCl₃) δ 7.37–7.19 (m, 5H), 7.15 (dd, J = 7.4, 1.8 Hz, 1H), 7.09 (dd, J = 8.0, 7.6, 1.8 Hz, 1H), 6.99 (ddd, J = 7.6, 7.4, 1.2 Hz, 1H), 6.87 (dd, J = 8.0, 1.2 Hz, 1H), 6.28 (d, J = 1.6 Hz, 1H), 5.51 (dd, J = 1.6, 0.8 Hz, 1H), 5.42 (d, J = 16.2 Hz, 1H), 5.09 (d, J = 16.2 Hz, 1H), 3.48 (t, J = 7.4 Hz, 1H), 1.74–1.61 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 164.84, 140.21, 137.93, 136.89, 128.91, 128.78, 128.10, 127.46, 127.10, 126.50, 123.87, 123.03, 115.74, 47.22, 46.37, 30.33, 11.20. ESI-MS [M + H]⁺ = 278. Anal. calcd for C₁₉H₁₉NO: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.19; H, 6.94; N, 5.03%.

1-Benzyl-3-Methylidene-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-2-one (20m). White solid (132 mg, 91%) mp 79–81 °C. Rf: 0.9 (UV active, CH₂Cl₂ : EtOAc = 3 : 2). IR (neat) ν (cm⁻¹): 3033, 2968, 2950, 2901, 1665, 1629, 1597, 1494, 1453, 1369, 1186, 1016. ¹H NMR (250 MHz, CDCl₃) δ 7.48–7.31 (m, 5H), 7.27–7.18 (m, 2H), 7.14–7.06 (m, 1H), 6.98 (dd, J = 8.0, 1.3 Hz, 1H), 6.40 (d, J = 1.6 Hz, 1H), 5.59 (dd, J = 1.7, 0.8 Hz, 1H), 5.56 (d, J = 16.2 Hz, 1H), 5.09 (d, J = 16.2 Hz, 1H), 3.40 (d, J = 7.1 Hz, 1H), 1.98 (qd, J = 6.9, 6.8 Hz, 2H), 1.03 (d, J = 2.1 Hz, 3H), 1.01 (d, J = 2.1 Hz, 3H). ¹³C NMR (63 MHz, CDCl₃) δ 165.48, 139.45, 138.64, 137.00, 129.15, 128.83, 127.90, 127.56, 127.16, 126.62, 124.74, 122.73, 115.68, 52.32, 46.66, 33.97, 20.31, 19.33. ESI-MS [M + H]⁺ = 292. Anal. calcd for C₂₀H₂₁NO: C, 82.44; H, 7.26; N, 4.81. Found: C, 82.61; H, 7.29; N, 4.77%.

1-Benzyl-3-Methylidene-4-phenyl-1,2,3,4-tetrahydroquinolin-2-one (20o). Colourless oil (135 mg, 83%). Rf: 0.8 (UV active, CH₂Cl₂ : EtOAc = 2 : 1). IR (neat) ν (cm⁻¹): 3064, 3025, 1665, 1638, 1597, 1493, 1459, 1370, 1187, 941. ¹H NMR (250 MHz, CDCl₃) δ 7.37–7.19 (m, 8H), 7.19–7.09 (m, 4H), 7.06 (ddd, J = 7.5, 7.4, 1.2 Hz, 1H), 6.98 (dd, J = 8.1, 1.2 Hz, 1H), 6.38 (s, 1H), 5.69 (s, 1H), 5.36 (d, J = 16.2 Hz, 1H), 5.16 (d, J = 16.2 Hz, 1H), 4.97 (s, 1H). ¹³C NMR (63 MHz, CDCl₃) δ 164.78, 140.69, 140.40, 138.57, 136.61, 129.00, 128.78, 128.71, 128.12, 127.75, 127.34, 127.22, 127.13, 126.68, 124.46, 123.29, 116.11, 49.55, 46.07. ESI-MS [M + H]⁺ = 326. Anal. calcd for C₂₃H₁₉NO: C, 84.89; H, 5.89; N, 4.30. Found: C, 84.77; H, 5.92; N, 4.34%.

Cytotoxicity assay by MTT

Cytotoxicity of the compounds was assessed by the mitochondrial reduction assay on two leukemia cell lines, promyelocytic HL-60 and lymphoblastic NALM-6 and on one solid tumor-derived cell line, breast cancer MCF-7 adenocarcinomas. Cells were purchased from the European Collection of Cell Cultures (ECACC). Leukemia cells were cultured in RPMI 1640 medium, while MCF-7 cells in DMEM (Dulbecco's Modified Eagle Medium), both supplemented with 10% heat-inactivated fetal bovine serum (Invitrogen, Paisley, UK) and antibiotics (100 μg mL⁻¹ streptomycin and 100 U mL⁻¹ penicillin). Normal human umbilical vein endothelial cells (HUVECs) and all reagents for cell culture were purchased from Cascade Biologics (Portland, Oregon, USA). The HUVECs were cultured according to the manufacturer's instructions and the cells underwent 3–8 passages. Cells were grown in 37 °C in a humidified atmosphere of 5% CO₂ in air. Exponentially growing cells were seeded at 8 × 10³ per well on 96-well plates (Nunc, Roskilde, Denmark). After 24 h, the tested compounds (freshly prepared in DMSO and diluted with complete culture medium to obtain the concentration range from 10⁻⁷ to 10⁻³ M) were added and the plates were incubated for 48 h. Afterwards, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, 5 mg mL⁻¹ in PBS) was added and incubation was continued for 2 h. The metabolically active cells reduced MTT to blue formazan crystals. Then, the MTT-containing medium was carefully aspirated and 100 μL DMSO was added to dissolve the crystals. After shaking 10 min in the dark absorbance was read at 560 nm on an ELISA-plate reader (ELX 800, Bio-Tek, USA) and compared with control (untreated cells). The IC₅₀ values were calculated from concentration–response curves.

Acknowledgements

This work was financially supported by the National Science Centre Poland (project DEC-2012/07/B/ST5/02006).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra16673j

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