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

Article abstract of DOI:10.1039/c5ra16673j

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.

Full text of DOI:10.1039/c5ra16673j

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Novel synthesis and cytotoxic activity of 1,4-disubstituted 3-methylidene-3,4-
DOI: 10.1039/C5RA16673J
dihydroquinolin-2(1H)-ones
M. Pięta,a J. Kędzia,a A. Janecka,b D. K. Pomorska, b M. Różalski,c U. Krajewska,c T. Janecki*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 of N-alkylation of 3-
diethoxyphosphorylquinolin-2(1H)-one, Michael addition of various Grignard reagents to N-alkylated
3-diethoxyphosphorylquinolin-2(1H)-ones and Horner-Wadsworth-Emmons reaction of the obtained
adducts with formaldehyde. Effective synthesis of starting 3-diethoxyphosphorylquinolin-2(1H)-one
was also developed. Furthermore, obtained 3-methylidene-3,4-dihydroquinolin-2(1H)-ones were
evaluated for their cytotoxic activity.
Introduction
-Alkylidene- or -lactones 1 and corresponding -alkylidene- and -lactams 2 are a big class of
natural as well as synthetic compounds that display a broad spectrum of biological properties.1,2 It is
generally believed that the conjugated -alkylidene moiety incorporated onto the lactone or lactam
ring is crucial for their biological activities.3 Undoubtedly, -alkylidene--lactones constitute the
biggest and the best known group within this class. On the other hand, -alkylidene--lactams are
much less recognized and only recently the first natural humantenine-type alkaloid containing this
moiety, gelegamine B 3, was isolated from Gelsemium elegan, a liane growing in Southeast Asia.4 On
the other hand, many synthetic -alkylidene--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 -alkylidene--lactam moiety.
Fig. 1 Structures of -alkylidene- and -lactons and lactams
a Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź,
Poland, E-mail: tomasz.janecki@p.lodz.pl, tel. (48)426313220, Fax: (+48)426365530
b Department of Biomolecular Chemistry, Medical University of Łódź, Mazowiecka 6/8, 92-215 Łódź,
Poland
c Department of Pharmacutical Biochemistry, Medical University of Łódź, Muszyńskiego 1, 90-151
Łódź, Poland
 Electronic Supplementary Information (ESI) available:

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A literature survey revealed that 3-alkylidene-3,4-dihydroquinolin-2(1H)-ones 4 were usually
DOI: 10.1039/C5RA16673J
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
10
sequence to 2-(2-nitrobenzyl)acrylate. 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 -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. Dissapointingly, 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, 0OC, 45 min.; (b) piperidine, toluene,
reflux, 8h.

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To obtain the amide 7 in a reasonable yield we performed an optimization of its synthesis changing
DOI: 10.1039/C5RA16673J
solvents, bases and temperature. However, even in the optimized conditions (toluene, 1.2 mol
equivalent of 2,6-lutidine, 0oC, 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, 0OC to rt, 5h; (b) Fe
dust, AcOH, 6h.

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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 broDmOiId: 1e0s.10in39/tCh5eRA16673J
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, 6-24h.
Table 1 Synthesis of 1-alkyl-3-diethoxyphosphorylquinolin-2-ones 16a-d and 2-alkoxy-3-
diethoxyphosphorylquinolines 17b-d.
Compound
Alkyl halide
16/17
Ratioa
>95:5
85:15
80:20
85:15
16b
Yield [%]
66
17b
Yield [%]
a
b
c
MeI
EtI
n-BuI
BnBr
-
61
59
70
14
13
10
d
a Taken from the 31P NMR spectrum of the crude product.
b Yield of isolated, purified product, based on 8.
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
3
characterized (Table2). Configurational assignments were made on the bases of diagnostic JH3H4
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
3
to determine JH3H4 = 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. 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,

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the mechanism of the formation of dephosphorylated quinolin-2-ones 19 is unclear and its
DOI: 10.1039/C5RA16673J
explanation needs further investigation.
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
1
separate and purify. However, H NMR spectrum of partially purified reaction mixture revealed
signals which could be attributed to 1-benzyl-3-methyl-4-vinyl-1,2-dihydroquinolni-2(1H)-one,
apparently originated from the isomerization of the initially formed 3-methylidene-3,4-
dihydroquinolin-2(1H)-one 20n.
Scheme 5 Reagents and conditions: (a) Grignard reagent, THF, rt, 2h; (b) paraformaldehyde, NaH,
THF, rt, 4h.
Table 2 Synthesis of 3-diethoxyphosphorylquinolin-2(1H)-ones 18a-o and 3-methylidene-3,4-
dihydroquinolin-2(1H)-ones 20a-m,o
Compound
R1
R2
18
trans/cis ratioa
>95 : 5
93 : 7
trans-18b
Yield [%]
73
20b
Yield [%]
82
a
b
c
d
e
f
g
h
i
Me
Me
Me
Et
Et
Et
Et
i-Pr
Ph
Me
Et
i-Pr
Ph
Et
43
87
>95 : 5
75 : 25
>95 : 5
>95 : 5
>95 : 5
>95 : 5
>95 : 5
>95 : 5
80 : 20
52/75c
56
90d
80
88
92
89
73
92
91
94
94
50
Et
45/65c
85
n-Bu
n-Bu
n-Bu
Bn
i-Pr
Ph
Me
41
j
k
57/91c
54

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DOI: 10.1039/C5RA16673J
l
m
n
o
Bn
Bn
Bn
Bn
Et
>95 : 5
92 : 8
>95 : 5
>95 : 5
58
65
96
91
-
83
i-Pr
vinyl
Ph
21
58/79c
a Taken from the 31P NMR spectrum of the crude product.
b Yield of isolated, purified product, based on 16 or 18, respectively.
cIn the presence of 0.1 eq of Cu2I2.
dCompound 20c is known (ref. 7).
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 Table3. 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 M
(25b, against MCF-7 cells) to 405 M (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 M against
all three cell lines display compounds 20h-n 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,n are
among the most active compounds and have IC50 values in the range between 40M and 100 M
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
R1
R2
IC50a (M)
HL-60
Compound
20
NALM-6
238±15
331±22
61.0±3.9
289±33
166±19
96.7±4.2
54.0±5.4
72.7±5.8
58.7±3.6
47.2±5.8
61.5±6.6
96.6±4.2
54.4±5.6
43.6±4.1
0.7±0.3
MCF-7
216±18
40.2±3.1
100±6.4
156±22
233±29
70.3±5.8
60.2±4.8
88.3±7.7
65.3±4.7
70.3±5.7
72.9±4.4
200±17
101±15
74.3±6.9
3.8±0.45
a
b
c
d
e
f
g
h
i
j
k
l
m
o
Me
Me
Me
Et
Et
Et
Et
i-Pr
Ph
Me
Et
i-Pr
Ph
Et
i-Pr
Ph
Me
Et
i-Pr
Ph
-
228±19
183±12
69.9±3.2
304±15
114±16
128±13
61.5±3.5
60.3±7.2
75.9±7.4
55.4±2.6
66.4±4.5
405±33
61.3±5.4
48.0±4.9
2.9±0.1
Et
n-Bu
n-Bu
n-Bu
Bn
Bn
Bn
Bn
-
Carboplatin
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.
Conclusions

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We have developed simple, general and efficient method for the synthesis of biologically important
DOI: 10.1039/C5RA16673J
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 M. It is worth to stress that cytotoxicity of 3-methylidenedihydroquinolin-2-ones haven’t
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.
1. Synthesis of 3-diethoxyphosphorylquinolin-2(1H)-one 8
1.1. Synthesis of 3-diethoxyphosphorylquinolin-2(1H)-one 8 from o-aminobenzaldehyde (5)
1.1.1 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

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removed in vacuo to yield a crude product which was purified by column chromatography (eluent:
DOI: 10.1039/C5RA16673J
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
1
ppm. H 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[14.8.0.0² ⁷.0⁸ ¹⁷.0¹⁰ ¹⁵.0¹⁸ 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 ⁰C. 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 (250MHz 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 (63MHz 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.
1.1.2 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 ⁰C. 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.
1.2. Synthesis of 3-diethoxyphosphorylquinolin-2(1H)-one 8 from o-nitrobenzaldehyde (13)
1.2.1 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

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mixture was slowly warmed to rt and stirred for 4 h. Then water was added (100 mL) and the mixture
DOI: 10.1039/C5RA16673J
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 (6.02g, 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.
1.2.2. 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 ⁰C 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*15mL), 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%).
2. 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 16 d) or for 8h (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 50-52⁰C. 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]+ =

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296; [M+Na]+ = 318. Anal. Calcd for C14H18NO4P: C, 56.95; H, 6.14; N, 4.74. Found: C, 57.05; H, 6.15;
DOI: 10.1039/C5RA16673J
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,
1
1638, 1616, 1562, 1449, 1242, 1219, 1049, 1019. 31P NMR (101 MHz, CDCl3) δ 14.67 ppm. H 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,
1
1618, 1592, 1416, 1338, 1252, 1074, 1019. 31P NMR (101 MHz, CDCl3) δ 15.16 ppm. H 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 ⁰C. 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,

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2931, 2905, 1641, 1563, 1450, 1241, 1223, 1049, 1020, 959. 31P NMR (101 MHz, CDCl3) δ 14.18 ppm.
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DOI: 10.1039/C5RA16673J
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,
1
2905, 1617, 1592, 1411, 1341, 1249, 1075, 1018, 964. 31P NMR (101 MHz, CDCl3) δ 15.05 ppm. H
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.
3. 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
1
22.64 ppm. H 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
1
(101 MHz, CDCl3) δ 23.28 ppm. H NMR (250 MHz, CDCl3) δ 7.26 (ddd, J = 8.1, 7.5, 1.7 Hz, 1H), 7.17

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(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 (sDpO, IJ: 1=0.160.399/HC5zR,A16673J
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 ⁰C.
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, 4 H), 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

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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,
DOI: 10.1039/C5RA16673J
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,
1
CDCl3) δ 22.02 ppm. H 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,
1
CDCl3) δ 22.68 ppm. H 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

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(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),
DOI: 10.1039/C5RA16673J
15.56 (d, J = 6.3 Hz), 13.42, 10.96. ESI-MS [M+H]+ = 368, [M-H]- = 366.Anal. Calcd for C H30NO4P: C,
19
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,
1
1640, 1625, 1595, 1455, 1207. H 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,

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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),
DOI: 10.1039/C5RA16673J
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 ⁰C. 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.
1
31P NMR (101 MHz, CDCl3) δ 22.72 ppm. H 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,
1
3031, 2959, 2870, 1640, 1593, 1495, 1453, 1226, 1207, 1069, 971. H 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. 31
NMR (101 MHz, CDCl3) δ 22.07 ppm. H 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,
P
1

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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),
DOI: 10.1039/C5RA16673J
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.
1
31P NMR (101 MHz, CDCl3) δ 21.53 ppm. H 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.
4. General procedure for the synthesis of 1,4-alkil or aryl 3-methylidene-1,2,3,4-
tetrahydroquinolin-2-ones 20a-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,
1
1497, 1459, 1351, 1112, 1050. H 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 ⁰C. Rf: 0.9 (UV active, CH2Cl2 : EtOAc = 3:2). IR (neat) ν (cm−1): 2977, 2964, 2909,
1
2867, 1666, 1636, 1596, 1471, 1350, 1120, 1049. H 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

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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,
DOI: 10.1039/C5RA16673J
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 ⁰C. Rf: 0.9 (UV active, CH2Cl2 : EtOAc = 3:2). IR (neat) ν (cm−1): 3052, 3021, 2922,
1
2849, 1671, 1633, 1597, 1454, 1352, 1110, 945. H 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 ⁰C. Rf: 0.9 (UV active, CH2Cl2 : EtOAc = 3:2). IR (neat) ν (cm−1): 2958, 1664, 1624, 1575,
1
1368, 1258, 1127. H 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,
1
1495, 1461, 1372, 1256, 1123. H 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,
1
1597, 1493, 1459, 1371, 1256, 1114. H 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,

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127.45, 127.13, 123.76, 123.07, 115.06, 49.67, 37.52, 12.57. ESI-MS [M+H]+ = 264. Anal. Calcd for
DOI: 10.1039/C5RA16673J
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,
1
1494, 1457, 1366, 1205, 1140. H 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,
1
1599, 1456, 1375, 1321, 1112. H 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,
1
1597, 1367, 1318, 1186. H 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 ⁰C. 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

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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
DOI: 10.1039/C5RA16673J
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 79-81⁰C. Rf: 0.9 (UV active, CH2Cl2 : EtOAc = 3:2). IR (neat) ν (cm−1): 3033, 2968, 2950,
1
2901, 1665, 1629, 1597, 1494, 1453, 1369, 1186, 1016. H 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,
1
1459, 1370, 1187, 941. H 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 streptomycin and 100 U/ml
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 ºC in a humidified atmosphere of 5% CO2 in air. Exponentially growing cells were seeded at
8×103/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 in PBS) was added and

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incubation was continued for 2h. The metabolically active cells reduced MTT to blue formazan
DOI: 10.1039/C5RA16673J
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 of Poland (project DEC-
2012/07/B/ST5/02006).
Notes and references
1. Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K.; Angew. Chem. Int. Ed. 2009, 48, 9426-9452.
2. Albrecht, A.; Albrecht, Ł.; Janecki, T.; Eur. J. Org. Chem. 2011, 15, 2747-2766.
3. (a) Zhang, S.; Won, Y.-K.; Ong, C.-N.; Shen, H.-M.; Curr. Med. Chem.: Anti-Cancer Agents 2005, 5,
239-249; (b) Janecka, A.; Wyrębska, A.; Gach, K.; Fichna, J.; Janecki, T.; Drug Disc. Today 2012, 17,
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16. Compound 20c has been reported in ref. 7.