Synthesis of 3-Hydroxy-4-arylquinolin-2-ones Including Viridicatol via a Darzens Condensation/Friedel-Crafts Alkylation Strategy

Article abstract of DOI:10.1021/acs.joc.8b01871

The new efficient synthesis of biologically important 3-hydroxy-4-arylquinolin-2-ones through the Darzens condensation (epoxidation) of dichloroacetanilides with aromatic aldehydes followed by one-pot dechlorative epoxide-arene cyclization is described. T

Full text of DOI:10.1021/acs.joc.8b01871

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Article
Synthesis of 3-Hydroxy-4-arylquinolin-2-ones Including Viridicatol
via a Darzens Condensation – Friedel-Crafts Alkylation Strategy
Vakhid A. Mamedov, Vera L. Mamedova, Saniya F. Kadyrova, Venera R. Galimullina,
Gul’naz Z. Khikmatova, Dmitry E Korshin, Aidar T. Gubaidullin, Dmitry B. Krivolapov,
Il'dar Kh. Rizvanov, Olga B. Bazanova, Oleg G. Sinyashin, and Shamil K. Latypov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01871 • Publication Date (Web): 01 Oct 2018
Downloaded from http://pubs.acs.org on October 4, 2018
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Synthesis of 3-Hydroxy-4-arylquinolin-2-ones Including Viridicatol
via a Darzens Condensation – Friedel-Crafts Alkylation Strategy
a,b
a,b
a,b
a
Vakhid A. Mamedov,* Vera L. Mamedova, Saniya F. Kadyrova, Venera R. Galimullina,
Gul’naz Z. Khikmatova, Dmitry E. Korshin, Aidar T. Gubaidullin, Dmitry B. Krivolapov,
Il'dar Kh. Rizvanov, Olga B. Bazanova, Oleg G. Sinyashin, and Shamil K. Latypov
a,b
a,b
a
a
a
a
b
a
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a
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of Russian Academy of
Sciences, Arbuzov str. 8, 420088 Kazan, Russian Federation, e-mail: mamedov@iopc.ru
b
Kazan National Research Technological University, Karl Marx str. 68, 420015 Kazan, Russian
Federation
ABSTRACT: The new efficient synthesis of biologically important 3-hydroxy-4-arylquinolin-2-ones through the Darzens
condensation (epoxidation) of dichloroacetanilides with aromatic aldehydes followed by one-pot dechlorative epoxide-arene
cyclization is described. This methodology has been utilized for the synthesis of naturally occurring viridicatol, a fungal
metabolite isolated from penicillium species.
INTRODUCTION
1
-7
Functionalized 4-arylquinolin-2-ones are a valuable class of biologically active compounds. In
particular, 3-hydroxy-4-arylquinolin-2-ones, including fungal metabolites viridicatin,2
viridicatol, and 3-O-methylviridicatin, (Fig. 1) have attracted much attention. For example, 3-
O-methylviridicatin from the fungus Penicillium puberulum have been reported by Heguy and
co-workers to inhibit the replication of the human immunodeficiency virus (HIV) induced by the
tumor necrosis factor (TNF-α) with an IC50 of 2.5 μM. Desaubry and co-workers synthesized 3-
O-mеthylviridicatin analogues with improved anti-TNF-α properties. Furthermore, compounds
containing the 3-hydroxyquinolin-2-one skeleton have also been intensively studied as
pharmaceutical agents such as the anti-allergy agent TA-270, selective inhibitors of HIV-1
3
4
5
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8
9
reverse transcriptase, potent D-amino acid oxidase (DAAO) and mitogen-activated protein
MAP) kinase inhibitors, [ H]-glycine binding to rat cortical membranes inhibitors, and
maxi-K channel openers with antibacterial activities.
10
3
11
(
1
2
Figure 1. Representatives of 3-hydroxy-4-arylquinolin-2(1H)-ones
found in natural products.
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However, the synthesis of 3-hydroxy-4-quinolin-2-ones has remained largely unexplored: only
a few synthetic strategies have been developed for the construction of the skeleton. The first
1
3
14
Friedlander type condensations, was reported by Huntress and co-workers where 2-(N-
chloroacetamino)benzaldehyde was obtained by the reaction of 2-aminobenzaldehyde with
chloroacetic anhydride, which was then converted to 3-hydroxyquinolin-2(1H)-one in the
presence of a base (Scheme 1a). The transformation of cyclopenin and cyclopenol into
viridicatin and viridicatol through a decarboxylation/rearrangement process was realized by
White and Smith groups (Scheme 1b).15 About the rearrangement of benzo[6,7]-1,4-
diazepino[5,4-b]oxazole derivatives was reported by Tachikawa (Scheme 1c).
condensation process of diazomethane (Scheme 1d) and its derivatives (Scheme 1e) with
isatins was realized by Undheim, Pellicciari and Gois groups. Taking into account of the strategy
a regioselective ring expansion reaction of isatins with aldehydes
promoted by p-toluenesulfonylhydrazide has been developed to construct various 3-hydroxy-4-
arylquinolin-2(1H)-ones, which proceeds via an in situ generated α-aryl/heteroaryldiazomethane
was described by Kamal and Babu (Scheme 1f). Kappa and co-workers carried out the Pd-
сatalyzed coupling reactions (Scheme 1g).20 An intramolecular annulation reactions of the
readily available cyanoacetanilides through a one-pot Knoevenagel condensation/epoxidation of
cyanoacetanilides followed by decyanative epoxide-arene cyclization was reported by Kobayashi
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The
1
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18
17,18
that laid down in the works
1
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21
and Harayama (Scheme 1h). The synthesis from the readily avaible N-phenylacetoacetamide
derivatives through PhI(OCOCF
3
)
2
-mediated α-hydroxylation and
H
2
SO -promoted
4
2
2
intramolecular condensation was demonstrated by Du and Zhao (Scheme 1i). Although the
existing methods have their own merits in the preparation of certain 3-hydroxyquinolin-2-one
derivatives, the search for a general method that is applicable for the construction of the 3-
hydroxyquinolin-2-one ring bearing a variety of substituents would therefore be of significant
value.
Scheme 1. Methods for the Synthesis of the 3-Hydroxyquinolin-2-one Skeleton
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RESULTS AND DISCUSSION
Our strategy for the synthesis of the 3-hydroxy-4-arylquinolin-2-ones is outlined in Scheme 2,
2
3
where 4 is obtained from 3 via the intramolecular Friedel-Crafts alkylation. In turn, 3 can be
prepared from dichloroacetanilides 1 and aromatic aldehydes 2 under the Darzens condensation
2
4
conditions. We assumed that Cl atom would function not only as an electron-withdrawing
group at the condensation step (1 + 2 ® 3) but also as a leaving group from the epoxide moiety
with the intermediate formation of an enolizable ketone group at the cyclization step (3 ® 4).
The salient features of our method are as follows: (1) a variety of dichloroacetanilides 1 and
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aldehydes 2 are readily available; (2) only two steps are required for the rapid synthesis of 4 with
diverse substitution patterns; (3) facile isolation of 4 is accomplished by a simple aqueous
workup.
Scheme 2. Strategy for the Synthesis of 3-Hydroxy-4-arylquinolin-2-ones 4
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We first examined the reaction between 2,2-dichloro-N-methyl-N-phenylacetamide 1a and
aromatic aldehydes having different substituents on the aromatic ring and their various electronic
effects (Table 1). It is known, that the nature of substituents in aromatic aldehydes determines
the direction of reaction and the structure of the products of Darzens condensation.2
brief survey of reactions under standard Darzens condensation conditions, we found that the
desired 2-chloro-3-(3-nitrophenyl)-N-methyl-N-phenyloxirane-2-carboxamide 3d was obtained
as the sole product in 88% yield when 3-nitrobenzaldehyde 2d (entry 4) was used. In the case of
benzaldehyde 2a (entry 1) as a carbonyl component for Darzens condensation, the formation of
4b,25
After a
3
-chloro-N-methyl-2-oxo-N,3-diphenylpropanamide 5a took place as the main product along
with trace amounts of the corresponding oxirane-2-carboxamide 3a and 3-hydroxy-4-
phenylquinolin-2-one 4a. When 4-chloro- (2b) and 4-bromo- (2c) benzaldehydes (entries 2, 3)
were used as the carbonyl components the reactions proceeded with the formation of 3-(4-
chlorophenyl)-
phenylpropionamides as major products with the 3-hydroxyquinolin-2-one derivatives 4b and
c as minor products, respectively.
(5b)
and
3-(4-bromophenyl)-
(5c)
3-chloro-2-oxo-N-methyl-N-
4
Table 1. Selection of the Types of Desired Aldehydes 2
entry
2 (Ar)
2a (C
2b (4-ClC
2c (4-BrC
2d (3-O NC
3 (yield, %)
3a (traces)a
3b (0)
5 (yield, %)
5a (86)
5b (75)
5c (80)
4 (yield, %)
4a (traces)a
4b (8)
1
2
3
6
H )
5
6
H
4
)
)
6
H
4
3c (0)
3d (88)
4c (6)
4d (0)
4
2
6
H
4
)
5d (0)
a
1
Compounds 3a and 4a are detected in NMR H spectra of reaction mixtures.
Compounds with underlined numbers were characterized by X-ray diffraction (see SI).
The formation of three types of compounds in different ratios during the course of the reaction
of 2,2-dichloro-N-methyl-N-phenylacetamide 1a with various aromatic aldehydes 2a-d is due to
the degree of the stability of chloroepoxides 3 formed under the standard Darzens condensation.
This stability of chloroepoxides 3 depends on the nature of the substituents in the aromatic ring
in position 3 of epoxide ring. The presence of a strong electron-withdrawing nitro group (Table
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1
, entry 4) compensates for the effect of the electron-withdrawing chlorine atom in position 2 of
the epoxide ring which increases the stability of the epoxide ring (Scheme 3). In other cases
(Table 1, entries 1-3), due to the chlorine atom at position 2 of the epoxide ring, the O-C3 bond
is weakened, which makes the C3 atom of the epoxide ring sensitive to nucleophilic attack either
by chlorine anion leading to 5, or by the second carbon atom of an anilide benzene ring with the
formation of 4. With these results, it is evident that to achieve the goal we must use aromatic
aldehydes with the strong electron withdrawing groups.
1
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Scheme 3. Proposed Reaction Mechanism for the Darzens Condensaton and the formation of
4 and 5
With the optimized conditions identified for aromatic aldehydes, we examined the substrate
1
scope of the reaction with respect to the nitrogen (R ) substituents of dichloroacetanilides 1
1
(
Table 2, entry 1-9). The reaction showed remarkable tolerance to a range of substituents R with
2
markedly different steric and electronic properties in the cases of 1a-c (R = H). We examined
the reactions of the N-benzyl and N-4-methoxybenzyl derivatives 1b and 1c as these can be
readily deprotected. Notably, the large-scale reactions can also be conducted easily and
inexpensively. For example, the reaction proceeded cleanly and efficiently to afford 7.81 g of 3f
when carried out with 20 mmol (6.48 g) of 1c (entry 3). To expand the utility of this reaction, we
next examined the effect of methyl group in the position 4 of the aromatic ring 1 (entries 10-11).
The substituent was found to have no effect on the Darzens condensation, and in these cases the
formation of corresponding 3-(3-nitrophenyl)- (3m) and 3-(4-cyanophenyl)- (3n) 2-chloro-N-(4-
methoxybenzyl)-N-(p-tolyl)oxirane-2-carboxamides takes place, respectively, as white light-
yellow solids in high yields.
Table 2. Substrate Scope of Dichloroacetanilides 1
entry
1
2
3
4
5
6
7
8
1
R1
H
Ph
R2
H
H
H
H
H
H
H
H
2
Ar
product 3
yield, %
88
1a
1b
1c
1a
1b
1c
1a
1b
1c
1d
1d
2d
2d
2d
2e
2e
2e
2f
2f
2f
2d
2f
3-NO
2
2
2
2
2
2
C
6
6
6
6
6
6
H
H
H
H
H
H
4
4
4
4
4
4
3d
3e
3f
3g
3h
3i
3j
3k
3l
3-NO
3-NO
4-NO
4-NO
4-NO
C
C
C
C
C
75
89
71
72
87
65
62
86
4-MeOC
H
Ph
4-MeOC
H
6
H
H
4
4
6
4-CNC
4-CNC
4-CNC
6
H
4
Ph
6
6
H
H
4
4
9
10
1
4-MeOC
4-MeOC
4-MeOC
6
6
6
H
H
H
4
4
4
H
Me
Me
3-NO
2
C
6
H
4
3m
3n
89
87
1
4-CNC
6
H
4
Compound with underlined number was characterized by X-ray diffraction (see SI).
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The intramolecular Friedel-Crafts alkylation of anilides of arylchloroglycidic acids was carried
out according to our strategy (Scheme 2). Cyclization of epoxides 3d-l took place smoothly to
afford the desired quinolinones 4d-l in 91-99% yields (Table 3). Cyclization of epoxides 3m,n
was complicated by partial isomerization of them to 3-(3-nitrophenyl)- (5m) and 3-(4-
cyanophenyl)- (5n) 3-chloro-2-oxo-N-(4-methoxybenzyl)-N-(p-tolyl)propionamides under the
reaction conditions (Fig. 2). Products 4m,n were isolated by recrystallization from acetone, and
products 5m,n were isolated by evaporating the acetone filtrate followed by flash
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chromatography on silica gel column using CHCl
3
as eluent.
Table 3. Intramolecular Friedel-Crafts Alkylation
a
entry
R1
H
R2
H
H
H
H
H
H
H
H
H
Ar
3
3d
3e
3f
3g
3h
3i
product 4
yield , %
1
2
3
4
5
6
7
8
9
3-NO
2
2
2
2
2
2
C
6
6
6
6
6
6
H
H
H
H
H
H
4
4
4
4
4
4
4d
4e
4f
4g
4h
4i
4j
4k
4l
93 (94)
95 (92)
99 (91)
98 (97)
96 (94)
98 (93)
99 (97)
99 (95)
98 (91)
46
Ph
3-NO
3-NO
4-NO
4-NO
4-NO
C
C
C
C
C
4-MeOC
H
Ph
4-MeOC
H
6
H
H
4
4
6
4-CNC
4-CNC
4-CNC
6
H
4
3j
Ph
6
6
H
H
4
4
3k
3l
4-MeOC
4-MeOC
4-MeOC
6
6
6
H
H
H
4
4
4
1
1
0
1
Me 3-NO
2
C
6
H
4
3m
3n
4m
4n
Me 4-CNC
The products are obtained by two methods.
Compound with underlined number was characterized by X-ray diffraction (see SI).
6
H
4
48
a
Figure 2. Representatives of 3-(Aryl)-3-chloro-2-oxo-N-(4-methoxybenzyl)-N-(p-
tolyl)propionamides.
The structures of all the compounds (Fig. 3) were established by various 1D/2D NMR
correlation methods. First, the proton spin systems of the Ar1 (Q), Ar2 and N-CH R moieties
were identified by COSY method. The number of NOEs between protons of these fragments
allows unequivocally correlate their mutual spatial position and assign exactly protons of Q
moiety. Then all corresponding protonated carbons were established by H- C HSQC spectra.
2
6
2
1
13
1
15
And finally, upon H- N HSQC/HMBC connectivities structures of both halves up to C1 and C2
were established in the case of 3 and 5 compounds. Differentiation of 3 versus 5 was based on
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13C CSs of C1 and C2: while in 5 these carbons resonates in the low field region typical for
carbonyl carbons, in 3 the CSs of C2 are at higher fields (77-78 ppm) characteristic for epoxy
carbons. GIAO chemical shift calculations strongly supports the above conclusion (see Table 1
in SI).
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1
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1
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Figure 3. Numbering of Atoms and Designation of Aromatic Fragments in the Structures 3-5.
The first step of intramolecular Friedel-Crafts alkylation is the protonation of the oxirane
oxygen atom of the anilide of arylchloroglycidic acid 3d-n to a carbocation that undergoes an
electrophilic aromatic substitution in the second step. Subsequent proton transfer, elimination of
HCl and deprotonation of the carbon atom C4 give rise to the neutral substituted 4-
arylquinolinones 4d-n (Scheme 4).
Scheme 4. Proposed Reaction Mechanism
It should be pointed out that the intramolecular cyclization of N,3-diaryloxirane-2-
carboxamides proceed with the involvement of the acid-catalyzed Meinwald rearrangement in
its first stage and the intramolecular Friedel-Crafts alkylation processes in the second stage with
24b,25,28
the formation of 3-arylquinolin-2(1H)-ones,
but in the present intramolecular cyclization
of 2-chloro-N,3-diaryloxirane-2-carboxamides 3d-n the process proceeds directly with the
involvement of the intramolecular Friedel-Crafts alkylation with the formation of 4-arylquinolin-
-ones.
2
Darzens condensation was best performed under mild conditions using t-BuOK as the catalyst
o
(
equiv amount of t-BuOK, toluene, -45 C to rt, 24 h), and the intramolecular Friedel-Crafts
o
alkylation proceeded efficiently under optimized conditions (AcOH/H
2 h). It was noted that 4-arylquinolin-2-ones 4d-l in both cases were obtained as solid by simple
2
SO or CFCOOH, 65 C,
4
~
aqueous workup and did not require the purification, whereas 4n,m were easily purified by
recrystallization from acetone.
Finally, the conversion of the resulting 3-hydroxy-4-(3-nitrophenyl)-N-(4-methoxybenzyl)-
quinolin-2-one 4f to quinolinone with a free NH function and OH group in aromatic component
was examined (Scheme 5) to obtain viridicatol 8. Attempts to convert the amino derivative 6b to
viridicatol 8 or the amino derivative 7a to the hydroxy derivative 7b using the Bucherer
2
9
30
reaction or by heating them with H
3
PO at 210 °C, used for similar systems, have not been
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6
successful. We have developed two different sequences of three-step methods for converting 4f
to viridicatol 8, which in the key stage include the treatment of the amine by an aqueous solution
of sodium nitrite in the presence of sulfuric acid. As shown in Scheme 4, there is no principal
difference at what stage the protective group is removed, the nitro group is reduced to the amino
group and amino group is replaced by the hydroxy group. The total yield in both cases is
approximately the same (64 and 63%).
0
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2
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5
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6
7
8
9
0
Scheme 5. The Synthesis of Viridicatol
CONCLUSION
In summary, we have demonstrated a new and efficient approach for the synthesis of biologically
3
1
active 3-hydroxy-4-arylquinolin-2-ones 4 by fully exploiting the chlorooxirane groups of the
anilides of arylchloroglycidic acids 3. Substrates for the reactions are widely available or can be
readily prepared, thus greatly enhancing the synthetic potential of the method. The development
of synthetic applications is under investigation and will be reported in due course.
EXPERIMENTAL SECTION
General Information. All NMR experiments were performed with 600, 500 and 400 MHz
600.1, 500.1 and 400.1 MHz for H NMR; 150.9, 125.7 and 100.6 MHz for C NMR; 60.8 and
1
13
(
1
5
50.6 MHz for N NMR, respectively) spectrometers equipped with 5 mm diameter gradient
inverse broad band probehead and a pulsed gradient unit capable of producing magnetic field
-1
32
pulse gradients in the z-direction of 53.5 G cm , and were carried out at 303 K. DPFGROE
and TOCSY spectra were obtained using Hermite-shaped pulse for selective excitation.
1
Chemical shifts (δ in ppm) are referenced to the solvents DMSO-d (δ = 2.49 ppm for H and
6
1
3
1
13
3
9.5 ppm for C NMR) and CDCl
3
(δ = 7.24 ppm for H and 77.0 ppm for C NMR), to
(380.2 ppm) for N NMR spectra (conversion factor to NH : -380.2 ppm). The
quantum chemical calculations were performed using a Gaussian 98w software package. Full
geometry optimizations have been carried out within the framework of DFT (B3LYP) method
using 6-31G(d) basis sets. Chemical shifts (CSs) were calculated by the GIAO method at the
same level of theory. All data were referred to TMS ( C) and NH
were calculated under the same conditions.
The MALDI mass spectra were recorded on an Ultraflex III TOF/TOF mass spectrometer
Bruker Daltonic GmbH, Bremen, Germany) in the reflection mode with the registration of
1
5
external CD
3
NO
2
3
3
3
27
13
15
3
( N) chemical shifts, which
(
positively charged ions. Measurement were made in the range m/z 200-1000. The m/z values of
monoisotopic ions are given in the descriptions. Samples were dissolved in DMF or CHCl at
3
concentration 4 mg/mL. A solution of the matrix (p-nitroaniline, 2.5-dihydroxybenzoic acid) in
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acetonitrile at concentration 10 mg/mL was prepared. A calibration mixture of PEG-300
acetonitrile solution at concentration 1 mg/mL) or crown ethers (methanol solution at
concentration 1 mg/mL) were used to obtain high-resolution mass spectra. Samples were
deposited by the dried-droplet method. Matrix solution (0.5 mkL), analyte solution (0.5 mkL)
and calibration mixture solutions (0.5 mkL) were deposited on the metal target MTP
(
TM
AnchorChip .
Compounds 1а-d were prepared by the modification of a literature procedure from
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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3
4
dichloroacetylchloride and N-methyl-, N-benzylanilines or N-(4-methoxybenzyl)anilines. N-
Methyl- and N-benzylanilines are commercially available and were used without further
purification. N-(4-Methoxybenzyl)anilines were prepared in 2 step according to a literature
2
0
procedure.
Synthesis of N-(4-methoxybenzyl)anilines. Step 1 (Synthesis of Imines). To a round-bottom
flask, were introduced 4-methoxybenzaldehyde (5.44 g (4.84 mL), 40 mmol) and 60 mL of
water. Aniline or p-toluidine (40 mmol) was added in one portion and the flask was kept at rt
under vigorous stirring for 3 h. The crude precipitate was filtered and dried in air. Step 2
Reduction of Imines). To a stirred solution of the imines (15 mmol) obtained in accordance with
the above procedure in MeOH (75 mL) NaBH (1.13 g, 30 mmol) was added in portion at 25-32
C within 10 minutes and the resulting suspension stirred at same temperature for 4 h. The
(
4
°
reaction mixture was left overnight at room temperature. The mixture was poured into ice-cold
water (200 mL). The precipitate was filtered, washed with water and dried in air.
(
4-Methoxybenzyliden)-N-phenylimine.
o
o
35
o
36
o
37
Yield: 7.86 g (93%), light-yellow solid, mp 73-74 C (45-48 C; 49.5-50.1 C; 66-68 C ); IR
-
1
1
(
KBr): νmax 1603, 1568, 1508, 1248, 1164, 1023, 844, 765, 689 cm ; Н NMR (400 MHz,
CDCl ): δ 3.89 (s, 3H, OMe), 7.01 (d, J=8.6 Hz, 2H, H2,6-NPh), 7.25 (dd, J=7.3, 7.4 Hz, 1H,
H4-NPh); 7.31 (d, J=6.5 Hz, 2H, H3,5-Ar), 7.40 (dd, J=8.4, 7.4 Hz, 2H, H3,5-NPh), 7.98 (d,
J=6.3 Hz, 2H, H2,6-Ar), 8.43 (s, 1H, N=CH); Anal. Calcd for C14 13NO: C, 79.59; H, 6.20; N,
3
H
6
.63. Found: C, 79.62; H, 6.18; N, 6.67%.
4-Methoxybenzyliden-N-(4-tolyl)imine.
o
o
38
o
39
o
40
Yield: 8.20 g (91%), white solid, mp 100-101 C (95-96 C; 93-94 C; 83 C ); IR (KBr):
-
1 1
ν
3
max 1604, 1569, 1508, 1249, 1166, 1025, 838, 546 cm ; Н NMR (400 MHz, CDCl
Н, Ме), 3.89 (s, 3H, OMe), 7.00 (d, J=8.9 Hz, 2H, H3,5-Ar ), 7.18 (d, J=8.2 Hz, 2H, H3,5-
Ar ), J=7.19 (d, J=8.1 Hz, 2H, H2,6-Ar ), 7.89 (d, J=8.8 Hz, 2H, H2,6-Ar ), 8.42 (s, 1H, N=CH);
Anal. for C15 15NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.62; H, 6.68; N, 6.38%.
N-(4-methoxybenzyl)aniline.
3
): δ 2.39 (s,
1
2
2
1
H
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
o
41
Yield 3.18 g (99%), white solid, mp 72-73 C (65-67 C ); IR (KBr): νmax 3419, 1605, 1509,
-
1 1
1
250, 753 cm ; Н NMR (500 MHz, CDCl
3
): δ 3.84 (s, 3H, OMe), 4.29 (s, 3H, NCH ), 6.68 (d,
J=7.6 Hz, 2H, H2,6-NPh), 6.76 (dd, J=7.3, 7.3 Hz, 1H, H4-NPh), 6.92 (d, J=8.6 Hz, 2H, H3,5-
Ar), 7.22 (ddd, J=7.6, 7.4, 0.9 Hz, 2H, H3,5-NPh), 7.33 (d, J=8.6 Hz, 2H, H-2,6-Ar). Anal.Calcd
2
for C14
H
15NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 78.72; H, 6.98; N, 6.61%.
N-(4-methoxybenzyl)-p-toluidine.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
o
42
Yield 3.34 g (98%), white solid, mp 75-76 C (82-83 C ); IR (KBr): νmax 3378, 1613, 1510,
-
1 1
1300, 1237, 1179, 1028, 810 cm ; Н NMR (400 MHz, CDCl
OMe), 4.25 (s, 3H, NCH ), 6.62 (d, J=8.3 Hz, 2H, H2,6-Ar2), 6.89 (d, J=8.6 Hz, 2H, H3,5-Ar1),
.01 (d, J=8.2 Hz, 2H, H3,5-Ar2), 7.31 (d, J=8.6 Hz, 2H, H2,6-Ar1); Anal.Calcd for C15
C, 79.26; H, 7.54; N, 6.16. Found: C, 78.99; H, 7.68; N, 6.31%.
Amidation of 2,2-dichloroacetyl chloride. A solution of 2,2-dichloroacetyl chloride (4.72 g
3.1 mL), 32 mmol) in anhydrous ether (10 mL) was added at 0-5 C to a stirred mixture of
3
): δ 2.26 (s, 3H, Me), 3.82 (s, 3H,
2
7
H17NO:
o
(
anilines (30 mmol) and Et N (3.24 g (4.5 mL), 32 mmol) in ether (150 mL). The reaction
3
mixture was stirred for 2 h without external cooling and then slowly with stirring water (200 mL)
was added. The precipitate was filtered, washed with water and dried in air to afford desired
amides 1a and 1b. Products 1c and 1d did not precipitate after treatment of the reaction mixture
with water. In this case the organic phase was separated, washed with water (75 mL), dried over
Na
2
SO , filtered, and ether was removed in vacuum to afford the desired amides.
,2-Dichloro-N-methyl-N-phenylacetamide (1a).
4
2
o
Yield: 5.95 g (91%), white solid, mp 77 C; IR (KBr): νmax 1687; 1494, 1387, 801, 779, 701, 667,
-
1 1
645, 559 cm ; Н NMR (500 MHz, CDCl
J=8.1, 1.3 Hz, 2H, H2,6-Ph), 7.43-7.54 (m, 3H, H3,4,5-Ph); Anal. Calcd for C
9.57; H, 4.16; Cl, 32.51; N, 6.42. Found: C, 49.52; H, 4.18; Cl, 32.68; N, 6.39%.
3
): δ 3.36 (s, 3H, NMe), 5.90 (s, 1H, Cl
2
CH), 7.30 (dd,
9
H
9
Сl NO: C,
2
4
2
,2-Dichloro-N-benzyl-N-phenylacetamide (1b).
o
-1 1
Yield: 7.85 g (89%), white solid, mp 107-108 C; IR (KBr): νmax 1677, 1495, 1400, 701 cm ; Н
NMR (500 MHz, CDCl
Anal. Calcd for C15
Cl, 24.51; N, 4.42%.
,2-Dichloro-N-(4-methoxybenzyl)-N-phenylacetamide (1c).
3
): δ 4.93 (s, 2H, NCH
2
), 5.86 (s, 1H, Cl CH), 7.05-7.45 (m, 10H, 2Ph);
2
H
13Сl
2
NO: C, 61.24; H, 4.45; Cl, 24.10; N, 4.76. Found: C, 61.57; H, 4.46;
2
Yield: 9.43 g (97%), light brown thick oil, crystallizing upon prolonged standing (7 days or
more) at room temperature to light brown crystal, mp 58-59 C; IR: νmax 1683, 1513, 1494, 1404,
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5
249, 806, 701 cm ; Н NMR (400 MHz, CDCl
.82 (s, 1H, Cl CH), 6.81 (d, J=8.6 Hz, 2H, H3,5-Ar), 7.02 (ddd, J=7.8, 5.2, 1.7 Hz, 2H, H2,6-
NPh), 7.11 (d, J=8.6 Hz, 2H, 2,6-Ar), 7.35-7.45 (m, 3H, H3,4,5-NPh); Anal. Calcd for
NO : C, 59.28; H, 4.66; Cl, 21.87; N, 4.32. Found: C, 59.53; H, 4.58; Cl, 21.53; N,
.40%.
,2-Dichloro-N-(4-methoxybenzyl)-N-(4-tolyl)acetamide (1d).
3
): δ 3.80 (s, 3H, OMe), 4.85 (s, 2H, NCH ),
2
2
C
4
16
H
15Сl
2
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
1
Yield: 9.94 g (98%), light brown thick, IR: νmax 1686, 1613, 1513, 1249, 1177, 1032, 806 cm ;
1
Н NMR (400 MHz, CDCl
H, Cl CH), 6.81 (d, J=8.7 Hz, 2H, H3,5-Ar1), 6.90 (d, J=8.0 Hz, 2H, H3,5-Ar
Hz, 2H, 2,6-Ar1), 7.18 (d, J=7.9 Hz, 2H, H2,6-Ar2); Anal. Calcd for C17 NO
.07; Cl, 20.96; N, 4.14. Found: C, 60.54; H, 5.36; Cl, 21.03; N, 4.01.
Synthesis of 3-chloro-2-oxo-3-aryl-N-methyl-N-phenylpropionamides (5a-c). To a stirred
3
): δ 2.38 (s, 3H, Me), 3.80 (s, 3H, OMe), 4.83 (s, 2H, NCH
), 7.11 (d, J=8.6
: C, 60.37; H,
2
), 5.84 (s,
1
2
2
H
17Сl
2
2
5
solution of 2,2-dichloro-N-methyl-N-phenylacetamide (1a) (3.45 g, 16 mmol) and aldehyde 2a-c
(1.69 g, 16 mmol) in anhydrous toluene (300 mL) under a nitrogen atmosphere t-BuOK (2.15 g,
19 mmol) was added in portions at -45 C within 30 minutes and the resulting suspension stirred
o
at same temperature for 1 h. The reaction mixture was allowed to warm to room temperature for
3
h. The resulting pale-yellow mixture was stirred at this temperature for additional 3 h and left
overnight. The reaction mixture was quenched to ice water (300 mL). The organic layer was
separated, washed twice with water, brine (2×100 mL), dried over MgSO and the solvent was
removed in vacuum to give a yellowish viscous liquid, which solidified overnight. In the NMR
H spectrum of this mixture along with the main product 5 was detected in small amounts of by-
products 3 and 4 (Table 1). By flash chromatography on silica gel column using a mixture of
cyclohexane-AcOEt (49/1) as eluent was isolated analytically pure 3-chloro-2-oxo-3-aryl-N-
methyl-N-phenylpropanamides (5) and small amounts of 3-hydroxy-4-aryl-N-methylquinolin-2-
ones (4).
4
1
3
-Chloro-2-oxo-3-phenyl-N-methyl-N-phenylpropionamide (5a).
o
Yield 3.95 g (86%), light-yellow solid, mp 80-81 C; IR (KBr): νmax 1724, 1642; 1594, 1495,
): δ 3.31 (s, 3H, NMe), 6.10 (s, 1H, ClCH),
6.91 (dd, J=7.9, 1.7 Hz, 2H, H2,6-Ar1), 7.25-7.32 (m, 5H, H3,4,5-Ar1, H2,6-Ar2), 7.37 (d,
J=7.3 Hz, 2H, H3,5-Ar2), 7.46 (d, J=7.2, 7.2 Hz, 1H, H4-Ar2); C{ H} NMR (150.9 MHz,
CDCl ): d 189.1 (C2), 164.6 (C1), 140.8 (C1-Ar1), 133.3 (C1-Ar2), 129.33 (C4-Ar2), 129.27
C3-Ar1), 128.9 (C2-Ar2), 128.8 (C3-Ar2), 128.2 (C4-Ar1), 126.6 (C2-Ar1), 62.6 (C3), 37.1
-
1
1
097, 730, 722, 696 cm ; NMR (500 MHz, CDCl
3
1
3
1
3
(
(
C
1
5
+
NMe); N NMR (50.6 MHz, CDCl
Cs 419.9762; Found 419.9753.
-Chloro-2-oxo-3-(4-chlorophenyl)-N-methyl-N-phenylpropionamide (5b).
3
): δ 124.4; HRMS (MALDI-TOF) m/z: [M + Cs] Calcd for
16
H
3
14СlNO
2
o
Yield 5.53 g (75%), light-yellow solid, mp 89-90 C; IR (KBr): νmax 1725, 1641, 1596, 1495,
-
1 1
1088, 765, 697 cm ; Н NMR (500 MHz, CDCl
3
): δ 3.34 (s, 3Н, NMe), 6.01 (s, 1H, ClCH), 7.01
(dd, J=7.6, 1.9 Hz, 2H, H2,6-Ar1), 7.18 (d, J=8.4 Hz, 2H, H2,6-Ar2), 7.31-7.36 (m, 5H, H3,4,5-
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1
1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
Ar1, H3,5-Ar2); C{ H} NMR (150.9 MHz, CDCl
3
): d 189.0 (C2), 164.5 (C1), 140.9 (C1-Ar1),
1
35.5 (C4-Ar2), 132.0 (C1-Ar2), 130.3 (C2-Ar2), 129.4 (C3-Ar2), 129.1 (C3-Ar1), 128.4 (C4-
1
5
Ar1), 126.7 (C2-Ar1), 61.5 (C3), 37.2 (NMe); N NMR (50.6 MHz, CDCl3): δ 124.6; HRMS
+
(
4
MALDI-TOF) m/z: [M + Cs] Calcd for C16
53.9361, 455.9339.
-Hydroxy-4-(4-chlorophenyl)-N-methylquinolin-2-one (4b).
H
13Сl
2
NO Cs 453.9372, 455.9345; Found
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
o
22
Yield 0.37 g (8%), white solid, mp 242 C (244-246 C ); IR (KBr): νmax 3247, 1626, 1600,
-
1 1
1
270, 754 cm ; Н NMR (500 MHz, DMSO-d
Hz, 1H, H5-Q), 7.19 (dd, J=8.0, 7.2 Hz, 1H, H6-Q), 7.36 (dd, J=8.3, 1.4 Hz, 2H, H2,6-Ar), 7.47
ddd, J=8.5, 7.1, 1.4 Hz, 1H, H7-Q), 7.57 (d, J=8.5 Hz, 1H, H8-Q), 7.58 (dd, J=8.3, 11.4 Hz, 2H,
6
): d 3.79 (d, J=1.2 Hz, 3Н, NMe), 7.12 (d, J=8.1
(
13
1
H3,5-Ar), 9.33 (s, 1H, OH); C{ H} NMR (125.7 MHz, DMSO-d
Q), 134.3 (C8a-Q), 132.49 (C1-Ar), 132.47 (C4-Ar), 131.8 (C2-Ar), 128.5 (C3-Ar), 126.9 (C7-
Q), 124.7 (C5-Q), 122.6 (C6-Q), 121.7 (C4-Q), 121.0 (C4a-Q), 114.8 (C8-Q), 30.0 (NMe); N
6
): d 157.9 (C2-Q), 141.8 (C3-
1
5
+
NMR (50.6 MHz, DMSO-d
286.0629; Found 286.0635.
6
): δ 142.3; HRMS (MALDI-TOF) m/z: [M + H] Calcd for
C
16
H
13СlNO
2
3-Chloro-2-oxo-3-(4-bromophenyl)-N-methyl-N-phenylpropionamide (5c).
o
Yield: 6.72 g (80%), light-yellow solid, mp 81-82 C; IR (KBr): νmax 1735, 1653; 1593, 1493,
485, 1070, 780, 700, 508 cm ; Н NMR (400 MHz, CDCl
ClCH), 7.01 (dd, J=7.2, 1.3 Hz, 2H, H2,6-Ar1), 7.11 (d, J=8.5 Hz, 2H, H2,6-Ar2), 7.30-7.34 (m,
H, H3,4,5-Ar1), 7.46 (d, J=8.5 Hz, 2H, H3,5-Ar2); C{ H} NMR (100.6 MHz, CDCl
88.9 (C2), 164.4 (C1), 140.8 (C1-Ar1), 132.5 (C1-Ar2), 132.0 (C3-Ar2), 130.4 (C2-Ar2), 129.4
C3-Ar1), 128.4 (C4-Ar1), 126.6 (C2-Ar1), 123.6 (C4-Ar2), 61.5 (C3), 37.1 (NMe); HRMS
(MALDI-TOF) m/z: [M + Cs] Calcd for C16
-
1 1
1
3
): δ 3.33 (s, 3Н, NMe), 5.99 (s, 1H,
1
3
1
3
1
(
3
): d
+
H
13BrClNO Cs 497.8867, 499.8846; Found
2
497.8856, 499.8834.
3
-Hydroxy-4-(4-bromophenyl)-N-methylquinolin-2-one (4c).
o
o
20
Yield 0.32 g (6%), white solid, mp 248-250 C (252-254 C ); IR (KBr): νmax 3240, 1625, 1601,
-
1 1
1
1
270, 754 cm ; H NMR (500 MHz, DMSO-d
6
): d 3.78 (s, 3Н, NMe), 7.11 (dd, J=8.0, 1.3 Hz,
H, H5-Q), 7.19 (ddd, J=8.0, 7.1, 1.0 Hz, 1H, H6-Q), 7.30 (d, J=8.5 Hz, 2H, H2,6-Ar), 7.47
(ddd, J=8.5, 7.1, 1.5 Hz, 1H, H7-Q), 7.57 (d, 1H, J=8.0 Hz, 1H, H8-Q), 7.71 (d, J=8.5 Hz, 2H,
H3,5-Ar), 9.34 (s, 1H, OH); C{ H} NMR (125.7 MHz, DMSO-d6): d 157.9 (C2-Q), 141.8
C3-Q), 134.3 (C8a-Q), 132.9 (C1-Ar), 132.2 (C2-Ar), 131.4 (C3-Ar), 127.0 (C7-Q), 124.7 (C5-
Q), 122.6 (C6-Q), 121.8 (C4-Q), 121.1 (C4a-Q), 121.0 (C4-Ar), 114.8 (C8-Q), 30.0 (NMe); N
13
1
(
1
5
+
NMR (50.6 MHz, DMSO-d6): δ 141.7; HRMS (MALDI-TOF) m/z: [M + H] Calcd for
C
16
H
13BrNO
2
330.0124, 332.0105; Found 330.0131, 332.0114.
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General procedure for the preparation of N-substituted 2-chloro-3-aryl-N-
phenyloxirane-2-carboxamides (3). To a stirred solution of 2,2-dichloroacetamide 1 (20 mmol)
and aldehyde 2 (20 mmol) in anhydrous toluene (300 mL) under a nitrogen atmosphere t-BuOK
o
(2.45 g, 22 mmol) was added in portions at -45 C within 30 minutes and the resulting
suspension stirred at same temperature for 1 h. The reaction mixture was allowed to reach the
room temperature for 5 h. The mixture was stirred at this temperature for additional 3 h and left
overnight. The reaction mixture was quenched to ice water (100 mL). The organic layer was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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6
0
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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8
9
0
separated, washed twice with water, brine (2×100 mL), dried over MgSO . The organic layer
4
was evaporated under reduced pressure and the oily residue was diluted with dry i-PrOH (5 mL)
and left at the ambient temperature. During 3-8 h the crystals that precipitated were collected by
suction filtration, washed with i-PrOH (2×5 mL), dried in air to afford the analytically pure N-
substituted 2-chloro-3-aryl-N-phenyloxirane-2-carboxamides (3).
2
-Chloro-3-(3-nitrophenyl)-N-methyl-N-phenyloxirane-2-carboxamide (3d).
о
Yield: 5.86 g (88%), yellow solid, mp 146-148 С; IR (KBr): nmax 1726, 1655, 1532, 1352, 699
-
1 1
cm ; H NMR (600 MHz, CDCl
3
): d 3.39 (s, 3H, NMe), 4.18 (s, 1H, H3), 7.31 (d, J=7.7 Hz, 1H,
H6-Ar2), 7.39 (d, J=4.3 Hz, 2H, H2,6-Ar1), 7.46 (dd, J=7.9, 8.0 Hz, 1H, H5-Ar2), 7.50 (c, 1H,
13
1
H2-Ar2), 7.52-7.57 (m, 3H, H3,4,5-Ar2), 8.14 (d, J=8.2 Hz, 1H, H4-Ar3); C{ H} NMR (150.9
MHz, CDCl ): d 162.9 (C1), 147.8 (C3-Ar2), 141.5 (C1-Ar1), 133.2 (C1-Ar2), 132.7 (C6-Ar2),
30.0 (C3-Ar1), 128.98 (C4-Ar1), 128.95 (C5-Ar2), 127.5 (C2-Ar1), 123.8 (C4-Ar2), 122.0 (C2-
3
1
1
5
Ar2), 77.3 (C2), 63.0 (C3), 38.2 (NMe); N NMR (60.8 MHz, CDCl
HRMS (MALDI-TOF) m/z: [M + Cs] Calcd for C16
3
): δ 368 (NO
Cs 464.9613; Found 464.9632.
-Chloro-3-(3-nitrophenyl)-N-benzyl-N-phenyloxirane-2-carboxamide (3e).
2
), 122 (N1);
+
H13ClN
2
O
4
2
о
Yield: 6.13 g (75%), light-yellow solid, mp 124-126 С; IR (KBr): nmax 1672, 1531, 1352, 702
-
1 1
cm ; H NMR (600 MHz, CDCl
.17 (d, J=7.6 Hz, 2H, H2,6-Ar1), 7.23 (dd, J=7.6, 2.4 Hz, 2H, H2,6-Ar2), 7.28-7.35 (m, 4H,
H3,4,5-Ar2, H6-Ar3), 7.43-7.52 (m, 5H, H3,4,5-Ar1, H2,5-Ar3), 8.14 (d, J=8.2 Hz, 1H, H4-
3
): d 4.22 (s, 1H, H3), 4.86, 5.06 (AB, J=14.3 Hz, 2H, CH ),
2
7
13
1
Ar3); C{ H} NMR (150.9 MHz, CDCl
3
): d 162.9 (C1), 147.8 (C3-Ar3), 139.7 (C1-Ar1), 135.8
(C2-Ar2), 133.2 (C1-Ar3), 132.7 (C6-Ar3), 129.7 (C3-Ar1), 129.2 (C5-Ar3), 128.94 (C4-Ar1),
1
28.90 (C2-Ar2), 128.8 (C2-Ar1), 128.6 (C3-Ar2), 127.9 (C4-Ar2), 123.8 (C4-Ar3), 122.0 (C2-
+
Ar3), 77.6 (C2), 63.1 (C3), 54.0 (CH
2
); HRMS (MALDI-TOF) m/z: [M + Cs] Calcd for
C
22
H
17ClN
2
O
4
Cs 540.9926; Found 540.9909.
2-Chloro-3-(3-nitrophenyl)-N-(4-methoxybenzyl)-N-phenyloxirane-2-carboxamide (3f).
o
Yield: 7.81 g (89%), tan solid, mp 106-107 C; IR (KBr): nmax 1671, 1528, 1515, 1350, 1254,
-
1 1
7
03 cm ; H NMR (600 MHz, CDCl
J=14.1 Hz, 2H, CH ), 6.82 (d, J=8.7 Hz, 2H, H3,5-Ar2), 7.14 (d, J=8.8 Hz, 2H, H2,6-Ar2), 7.15
d, J=9.7 Hz, 2H, H2,6-Ar1), 7.30 (d, J=7.6 Hz, 1H, H6-Ar3), 7.43-7.52 (m, 5H, H3,4,5-Ar1,
3
): d 3.80 (s, 3H, OMe), 4.21 (s, 1H, H3), 4.80, 4.99 (AB,
2
(
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2
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5
5
5
5
5
5
6
1
3
1
H2,5-Ar3), 8.14 (d, J=8.2 Hz, H4-Ar3); C{ H} NMR (150.9 MHz, CDCl
3
): d 162.7 (C1),
1
59.3 (C4-Ar2), 147.7 (C3-Ar3), 139.6 (C1-Ar1), 133.2 (C1-Ar3), 132.6 (C2-Ar2), 130.3 (C2-
Ar2), 129.6 (C3-Ar1), 129.1 (C5-Ar3), 128.9 (C2-Ar1+C4-Ar1), 127.9 (C1-Ar2), 123.7 (C4-
Ar3), 121.9 (C2-Ar3), 113.9 (C3-Ar2), 77.6 (C2), 63.0 (C3), 55.1 (OMe), 53.4 (CH ); HRMS
2
+
(
MALDI-TOF) m/z: [M + Cs] Calcd for C23
H
19ClN
2
O Cs 571.0031; Found 571.0046.
5
2
-Chloro-3-(4-nitrophenyl)-N-methyl-N-phenyloxirane-2-carboxamide (3g).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Yield: 4.72 g (71%), tan solid, mp 141-143 С; IR (KBr): nmax 1671, 1520, 1346, 956, 705 cm-1;
H NMR (600 MHz, CDCl ): d 3.39 (s, 3H, NMe), 4.20 (s, 1H, H3), 7.03 (d, J=8.4 Hz, 2H,
H2,6-Ar2), 7.39 (d, J=7.4 Hz, 2H, H2,6-Ar1), 7.46-7.56 (m, 3H, H3,4,5-Ar1), 8.11 (d, J=8.4 Hz,
2H, H3,5-Ar2); C{ H} NMR (150.9 MHz, CDCl
о
1
3
1
3
1
3
): d 162.8 (C1), 148.2 (C4-Ar2), 141.7 (C1-
Ar1), 138.1 (C1-Ar2), 130.0 (C3-Ar1), 128.7 (C4-Ar1), 127.9 (C2-Ar2), 127.6 (C2-Ar1), 123.0
+
(
C
C3-Ar2), 77.4 (C2), 63.0 (C3), 38.3 (NMe); HRMS (MALDI-TOF) m/z: [M + Cs] Calcd for
Cs 464.9613; Found 464.9630.
-Сhloro-3-(4-nitrophenyl)-N-benzyl-N-phenyloxirane-2-carboxamide (3h).
16
H
13ClN
2
O
4
2
о
Yield: 5.89 g (72%), light-yellow solid, mp 123-124 С; IR (KBr): nmax 1669, 1521, 1348, 700
-1
1
cm ; H NMR (500 MHz, CDCl
.01 (d, J=8.7 Hz, 2H, H2,6-Ar3), 7.19 (dd, J=7.9, 2.3 Hz, 2H, H2,6-Ar1), 7.22 (dd, J=7.6, 2.8
Hz, 2H, H2,6-Ar2), 7.26-7.32 (m, 3H, H3,4,5-Ar2), 7.41-7.47 (m, 3H, H3,4,5-Ar1), 8.09 (d,
3
): d 4.27 (s, 1H, H3), 4.87, 5.06 (AB, J=14.2 Hz, 2H, CH ),
2
7
1
3
1
J=8.7 Hz, 2H, H3,5-Ar3); C{ H} NMR (125.7 MHz, CDCl ): d 162.8 (C1), 148.1 (C4-Ar3),
139.7 (C1-Ar1), 138.0 (C1-Ar3), 135.8 (C1-Ar2), 129.6 (C3-Ar1), 128.8 (C2-Ar2+C2-Ar1+C4-
Ar1), 128.6 (C3-Ar2), 127.9 (C4-Ar2), 127.8 (C2-Ar3), 123.0 (C3-Ar3), 77.6 (C2), 63.0 (C3),
3
15
+
5
4.0 (CH
2
); N NMR (50.6 MHz, CDCl ): δ 137 (N1); HRMS (MALDI-TOF) m/z: [M + Cs]
Cs 540.9926; Found 540.9947.
-Chloro-3-(4-nitrophenyl)-N-(4-methoxybenzyl)-N-phenyloxirane-2-carboxamide (3i).
3
Calcd for C22
H
17ClN
2
O
4
2
о
Yield: 7.63 g (87%), white solid, mp 114-115 С; IR (KBr): nmax 1672, 1523, 1349, 1251, 700
-1
1
cm ; H NMR (600 MHz, CDCl
J=14.2 Hz, 2H, CH ), 6.82 (d, J=8.4 Hz, 2H, H3,5-Ar2), 7.00 (d, J=8.3 Hz, 2H, H2,6-Ar3), 7.13
d, J=8.5 Hz, 2H, H2,6-Ar2), 7.16 (d, J=7.3 Hz, 2H, H2,6-Ar1), 7.42-7.47 (m, 3H, H3,4,5-Ar1),
3
): d 3.80 (s, 3H, OMe), 4.23 (s, 1H, H3), 4.81, 4.97 (AB,
2
(
8
1
3
1
.09 (d, J=8.3 Hz, 2H, H3,5-Ar3); C{ H} NMR (150.9 MHz, CDCl ): d 162.7 (C1), 159.3 (C4-
3
Ar2), 148.2 (C4-Ar3), 139.7 (C1-Ar1), 138.1 (C1-Ar3), 130.3 (C2-Ar2), 129.6 (C3-Ar1), 129.0
(C2-Ar1), 128.8 (C4-Ar1), 127.9 (C1-Ar2), 127.8 (C2-Ar3), 123.0 (C3-Ar3), 113.9 (C3-Ar2),
1
5
7
(
5
7.7 (C2), 63.1 (C3), 55.2 (OMe), 53.5 (CH
N1); HRMS (MALDI-TOF) m/z: [M + Cs] Calcd for C23
71.0046.
2
); N NMR (60.8 MHz, CDCl
3
): δ 368 (NO
2
), 138
+
H
19ClN
2
O
5
Cs 571.0031; Found
2
-Chloro-3-(4-cyanophenyl)-N-methyl-N-phenyloxirane-2-carboxamide (3j).
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Yield: 4.07 g (65%), white solid, mp 152-153 С; IR (KBr): nmax 2227, 1669, 1265, 675, 598 cm-
): d 3.37 (s, 3H, NMe), 4.15 (s, 1H, H3), 6.95 (d, J=7.9 Hz, 2H,
H2,6-Ar2), 7.37 (d, J=7.4 Hz, 2H, H2,6-Ar1), 7.47 (dd, J=6.9, 6.9 Hz, 1H, H4-Ar1), 7.50 (dd,
J=7.4, 6.9 Hz, 2H, H3,5-Ar1), 7.53 (d, J=7.8 Hz, 2H, H3,5-Ar2); C{ H} NMR (150.9 MHz,
CDCl ): d 162.8 (C1), 141.6 (C1-Ar1), 136.1 (C1-Ar2), 131.5 (C3-Ar2), 129.9 (C3-Ar1), 128.5
C4-Ar1), 127.6 (C2-Ar2), 127.5 (C2-Ar1), 118.2 (CN), 112.7 (C4-Ar2), 77.4 (C2), 63.1 (C3),
): δ 122 (N1). HRMS (MALDI-TOF) m/z: [M + Cs]
Calcd for C17 Cs 444.9715; Found 444.9728.
о
1
1
;
H NMR (600 MHz, CDCl
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
3
(
3
15
+
8.2 (NMe); N NMR (60.8 MHz, CDCl
3
H
13ClN
2
O
2
2
-chloro-3-(4-cyanophenyl)- N-benzyl-N-phenyloxirane-2-carboxamide (3k).
о
-1 1
Yield: 4.82 g (62%), white solid, mp 124-125 С; IR (KBr): nmax 2229, 1668, 698 cm ; H NMR
(
2
7
500 MHz, CDCl
3
): d 4.21 (s, 1H, H3), 4.87, 5.04 (AB, J=14.2 Hz, 2H, CH
H, H2,6-Ar3), 7.17 (dd, J=7.6, 3.8 Hz, 2H, H2,6-Ar1), 7.22 (dd, J=7.2, 3.0 Hz, 2H, H2,6-Ar2),
.28-7.35 (m, 3H, H3,4,5-Ar2), 7.40-7.45 (m, 3H, H3,4,5-Ar1), 7.54 (d, J=8.0 Hz, 2H, H3,5-
C{ H} NMR (125.7 MHz, CDCl ): d 162.9 (C1), 139.8 (C1-Ar1), 136.2 (C1-Ar3),
135.8 (C1-Ar2), 131.6 (C3-Ar3), 129.6 (C3-Ar1), 128.9 (C2-Ar1+C2-Ar2), 128.8 (C4-Ar1),
28.6 (C3-Ar2), 127.9 (C4-Ar2), 127.6 (C2-Ar3), 118.2 (CN), 112.8 (C4-Ar3), 77.8 (C2), 63.2
2
), 6.97 (d, J=8.0 Hz,
1
3
1
Ar3);
3
1
(
15
C3), 54.1 (CH
2
); N NMR (50.6 MHz, CDCl
Cs] Calcd for C23 Cs 521.0028; Found 521.0049.
-Chloro-3-(4-cyanophenyl)-N-(4-methoxybenzyl)-N-phenyloxirane-2-carboxamide (3l).
3
): δ 137 (N1); HRMS (MALDI-TOF) m/z: [M +
+
H17ClN
2
O
2
2
о
Yield: 6.03 g (72%), white solid, mp 123-124 С; IR (KBr): nmax 2231, 1670, 1513, 1251, 579
-1
1
cm ; H NMR (500 MHz, CDCl
J=14.0 Hz, 2H, CH ), 6.83 (d, J=8.7 Hz, 2H, H3,5-Ar2), 6.96 (d, J=8.4 Hz, 2H, H2,6-Ar3), 7.10-
.16 (m, 4H, H2,6-Ar1, H2,6-Ar2), 7.40-7.46 (m, 3H, H3,4,5-Ar1), 7.54 (d, J=8.3 Hz, 2H, H3,5-
3
): d 3.81 (s, 3H, OMe), 4.18 (s, 1H, H3), 4.82, 4.97 (AB,
2
7
1
3
1
Ar3); C{ H} NMR (125.7 MHz, CDCl ): d 162.8 (C1), 159.3 (C4-Ar2), 139.7 (C1-Ar1), 136.3
(C1-Ar3), 131.6 (C3-Ar3), 130.4 (C2-Ar2), 129.6 (C3-Ar1), 129.0 (C2-Ar1), 128.8 (C4-Ar1),
128.2 (C1-Ar2), 127.6 (C2-Ar3), 118.2 (CN), 114.0 (C3-Ar2), 112.8 (C4-Ar3), 77.8 (C2), 63.2
3
+
(
C
C3), 55.2 (OMe), 53.6 (CH
Cs 551.0133; Found 551.0156.
-Chloro-3-(3-nitrophenyl)-N-(4-methoxybenzyl)-N-(4-tolyl)oxirane-2-carboxamide (3m).
2
); HRMS (MALDI-TOF) m/z: [M + Cs] Calcd for
24
H
19ClN
2
O
3
2
о
Yield: 7.70 g (85%), light-yellow solid, mp 134-135 С; IR (KBr): nmax 1672, 1528, 1513, 1348,
252 cm ; H NMR (600 MHz, CDCl ): d 2.44 (s, 3H, Me), 3.79 (s, 3H, OMe), 4.19 (s, 1H,
-
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1
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H3), 4.75, 4.96 (AB, J=14.1 Hz, 2H, CH
H, H2,6-Ar1), 7.13 (d, J=8.6 Hz, 2H, H2,6-Ar2), 7.25 (d, J=8.0 Hz, 2H, H3,5-Ar1), 7.35 (d,
J=7.8 Hz, 1H, H6-Ar3), 7.42 (s, 1H, H2-Ar3), 7.45 (dd, J=8.0, 7.9 Hz, 1H, H5-Ar3), 8.13 (d,
2
), 6.82 (d, J=8.6 Hz, 2H, H3,5-Ar2), 7.01 (d, J=8.1 Hz,
2
1
3
1
J=8.1, 1H, H4-Ar3); C{ H} NMR (150.9 MHz, CDCl
C3-Ar3), 139.5 (C4-Ar1), 136.9 (C1-Ar1), 133.3 (C1-Ar3), 132.7 (C6-Ar3), 130.4 (C2-Ar2),
3
): d 162.8 (C1), 159.2 (C4-Ar2), 147.7
(
1
30.3 (C3-Ar1), 128.9 (C5-Ar3), 128.6 (C2-Ar1), 128.1 (C1-Ar2), 123.7 (C4-Ar3), 121.9 (C2-
), 21.1 (Me); HRMS
Cs 585.0188; Found 585.0170.
Ar3), 113.9 (C3-Ar2), 77.6 (C2), 63.1 (C3), 55.2 (OMe), 53.4 (CH
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(
MALDI-TOF) m/z: [M + Cs] Calcd for C24
H
21ClN
2
O
5
2-Chloro-3-(4-cianophenyl)-N-(4-methoxybenzyl)-N-(4-tolyl)oxirane-2-carboxamide (3n).
о
Yield: 7.53 g (87%), light-yellow solid, mp 139 С; IR (KBr): nmax 2227, 1668, 1611, 1512,
-
1 1
1
247, 1026, 956, 849, 578 cm ; H NMR (500 MHz, CDCl
OMe), 4.17 (s, 1H, H3), 4.78, 4.93 (AB, J=14.0 Hz, 2H, CH
Ar2), 6.97 (d, J=8.3 Hz, 2H, H2,6-Ar3), 7.01 (d, J=8.2 Hz, 2H, H2,6-Ar1), 7.13 (d, J=8.6 Hz,
2H, H2,6-Ar2), 7.21 (d, J=8.1 Hz, 2H, H3,5-Ar1), 7.54 (d, J=8.4 Hz, 2H, H3,5-Ar3); C{ H}
NMR (150.9 MHz, CDCl ): d 188.9 (C2), 164.0 (C1), 159.3 (C4-Ar2), 138.9 (C1-Ar3), 138.9
C4-Ar1), 136.2 (C1-Ar1), 132.4 (C3-Ar3), 130.2 (C2-Ar2), 129.9 (C3-Ar1), 129.6 (C2-Ar3),
3
): d 2.43 (s, 3H, Me), 3.81 (s, 3H,
2
), 6.83 (d, J=8.7 Hz, 2H, H3,5-
1
3
1
3
(
1
(
C
27.9 (C2-Ar1), 127.7 (C1-Ar2), 118.1 (CN), 113.9 (C3-Ar2), 113.2 (C4-Ar3), 61.3 (C3), 55.2
OMe), 52.8 (CH2), 21.1 (Me); HRMS (MALDI-TOF) m/z: Calcd for [M + Cs]+
25
H
21ClN
2
O
3
Cs 565.0290; Found 565.0294.
General procedure for the preparation of 3-hydroxy-4-arylquinolin-2-ones (4). Method A:
A suspension of oxirane-2-carboxamide 3d-n (5 mmol) in a mixture of acetic (10 mL) and
sulfuric (0.5 mL) acids was transferred to the solution by heating at 60 to 65 °C for 30 min. The
resulting solution was heated at this temperature with stirring for 2 h or until a precipitation took
place. The sediment precipitated after cooling the reaction mixture or during the process was
filtered, washed with water (3×10 mL), dried in air to afford the analytically pure 3-hydroxy-4-
arylquinolin-2-one 4d-l. The compounds 4m,n required additional purification. The crude
product was washed with acetone (2×3 mL). The collected by filtration and dried in air
compound corresponded to analytically pure 3-hydroxy-4-arylquinolin-2-one 4m,n. Products
m,n were isolated by evaporating the acetone filtrate followed by flash chromatography on
silica gel column using CHCl as eluent. Меthod В: A solution of oxirane-2-carboxamide 3d-l (5
mmol) in trifluoroacetic acid (10 mL) was heated at 60 to 65 ° C with stirring for 2 hour. The
sediment that precipitated upon the addition of water (30 mL) was filtered, washed with water,
and dried in air to afford the analytically pure 3-hydroxy-4-arylquinolin-2-one 4d-l.
5
3
3
-Hydroxy-4-(3-nitrophenyl)-N-methylquinolin-2-one (4d).
о
Yield: 1.38 g (93%) (1.39 g (94%)), white solid, mp 274-276 С; IR (KBr): nmax 3269, 1602,
-
1 1
1
525, 1346, 1283, 1268, 765 cm ; H NMR (600 MHz, CDCl
J=8.0, 7.0 Hz, 1H, H6-Q), 7.29 (dd, J= 8.0, 1.2 Hz, 1H, H5-Q), 7.48 (d, J=8.4 Hz, 1H, H8-Q),
.52 (ddd, J=8.3, 7.0, 1.4 Hz, 1H, H7-Q), 7.73 (ddd, J=7.9, 7.7, 1.7 Hz, 1H, H5-Ar), 7.80 (d,
3
): d 3.93 (s, 3H, NMe), 7.25 (dd,
7
1
3
1
J=7.7 Hz, 1H, H6-Ar), 8.34 (s, 1H, H2-Ar), 8.35 (d, J=8.0 Hz, 1H, H4-Ar); C{ H} NMR
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(
1
150.9 MHz, CDCl
3
): d 158.8 (C2), 148.6 (C3-Ar), 141.4 (C3), 136.4 (C6-Ar), 134.8 (C1-Ar),
34.5 (C8a), 129.6 (C5-Ar), 127.8 (C7), 125.4 (C5), 125.3 (C2-Ar), 123.5 (C6), 123.2 (C4-Ar),
121.1 (C4a), 120.5 (C4), 114.6 (C8), 30.6 (NMe); HRMS (MALDI-TOF) m/z: [M + H] Calcd
297.0870; Found 297.0863.
+
for C16
H
13
N
2
O
4
3
-Hydroxy-4-(3-nitrophenyl)-N-benzylquinolin-2-one (4e).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
о
Yield: 1.77 g (95%) (1.71 g (92%)), tan solid, mp 230-232 С; IR (KBr): nmax 3236, 1625, 1601,
-
1 1
1
528, 1346, 1265, 737 cm ; H NMR (500 MHz, CDCl ): d 5.73 (s, 2H, CH ), 7.20 (dd, J=7.5,
.4 Hz, 1H, H6-Q), 7.28-7.33 (m, 3H, H5-Q, H2,6-Ar1), 7.34-7.44 (m, 5H, H7,8-Q, H3,4,5-
Ar1), 7.76 (dd, J=7.9, 7.7 Hz, 1H, H5-Ar2), 7.84 (d, J=7.6 Hz, 1H, H6-Ar2), 8.37 (d, J=8.0 Hz,
1H, H4-Ar2), 8.39 (s, 1H, H2-Ar2); C{ H} NMR (125.7 MHz, CDCl
C3-Ar2), 141.3 (C3-Q), 136.4 (C6-Ar2), 135.4 (C1-Ar1), 134.8 (C1-Ar2), 133.9 (C8a-Q), 129.7
C5-Ar2), 129.0 (C3-Ar1), 127.8 (C7-Q), 127.7 (C4-Ar1), 126.6 (C2-Ar1), 125.5 (C5-Q), 125.3
C2-Ar2), 123.5 (C6-Q), 123.3 (C4-Ar2), 121.3 (C4-Q), 121.1 (C4a-Q), 115.5 (C8-Q), 47.3
3
2
7
1
3
1
3
): d 159.1 (C2-Q), 148.5
(
(
(
(
+
CH
2
); HRMS (MALDI-TOF) m/z: [M + H] Calcd for C22
H
17
N
2
4
O 373.1183; Found 373.1196.
3
-Hydroxy-4-(3-nitrophenyl)-N-(4-methoxybenzyl)quinolin-2-one (4f).
о
Yield: 1.99 g (99%) (1.83 g (91%)), white solid, mp 162-165 С; IR (KBr): nmax 3269, 1617,
-1
1
1
601, 1530, 1513, 1349, 1246, 744 cm ; H NMR (500 MHz, CDCl
s, 2H, CH ), 6.90 (d, J=8.5 Hz, 2H, H3,5-Ar1), 7.20 (dd, J=7.7, 7.2 Hz, 1H, H6-Q), 7.26 (d,
J=8.5 Hz, 2H, H2,6-Ar1), 7.29 (d, J=7.8 Hz, 1H, H5-Q), 7.40 (dd, J=8.1, 7.3 Hz, 1H, H7-Q),
.47 (d, J=8.3 Hz, 1H, H8-Q), 7.75 (dd, J=7.9, 7.7 Hz, 1H, H5-Ar2), 7.83 (d, J=7.6 Hz, 1H, H6-
3
): d 3.81 (s, 3H, OMe), 5.66
(
2
7
1
3
1
Ar2), 8.36 (d, J=8.0, 1H, H4-Ar2), 8.38 (s, 1H, H2-Ar2); C{ H} NMR (125.7 MHz, CDCl
3
): d
159.1 (C2-Q), 159.0 (C4-Ar1), 148.5 (C3-Ar2), 141.3 (C3-Q), 136.4 (C6-Ar2), 134.8 (C1-Ar2),
33.9 (C8a-Q), 129.7 (C5-Ar2), 128.1 (C2-Ar1), 127.8 (C7-Q), 127.5 (C1-Ar1), 125.4 (C5-Q),
25.3 (C2-Ar2), 123.5 (C6-Q), 123.3 (C4-Ar2), 121.4 (C4a-Q), 121.1 (C4-Q), 115.5 (C8-Q),
1
1
1
1
5
14.4 (C3-Ar1), 55.3 (OMe), 46.7 (CH
2
); N NMR (50.6 MHz, CDCl
3
): δ 153 (N1), 369 (NO
Cs 535.0265; Found 535.0283.
2
);
+
); HRMS (MALDI-TOF) m/z: Calcd for [M + Сs] C23
H
18
N
2
O
5
3
-Hydroxy-4-(4-nitrophenyl)-N-methylquinolin-2-one (4g).
о
о
22
Yield: 1.45 g (98%) (1.44 g (97%)), white solid, mp 284-285 С (276-278 С ); IR (KBr): nmax
256, 1626, 1600, 1513, 1347, 1267, 753 cm ; H NMR (500 MHz, CDCl ): d 3.94 (s, 3H,
-
1
1
3
3
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMe), 7.24-7.33 (m, 2H, H5,6-Q), 7.50 (d, J=8.3 Hz, 1H, H8-Q), 7.54 (ddd, J=8.4, 6.8, 1.6 Hz,
1
3
1
1
H, H7-Q), 7.65 (d, J=8.8 Hz, 2H, H2,6-Ar), 8.41 (d, J=8.8 Hz, 2H, H3,5-Ar); C{ H} NMR
(125.7 MHz, CDCl ): d 158.8 (C2-Q), 147.8 (C4-Ar), 141.1 (C3-Q), 140.0 (C1-Ar), 134.4 (C8a-
Q), 131.3 (C2-Ar), 127.9 (C7-Q), 125.5 (C5-Q), 123.8 (C3-Ar), 123.6 (C6-Q), 121.2 (C4-Q),
3
15
1
21.0 (C4a-Q), 114.6 (C8-Q), 30.7 (NMe); N NMR (50.6 MHz, CDCl
3
): δ 141 (N1), 369
297.0870; Found 297.0862.
+
(NO
2
); HRMS (MALDI-TOF) m/z: Calcd for [M + H] C16
-Hydroxy-4-(4-nitrophenyl)-N-benzylquinolin-2-one (4h).
H
13
N
2
O
4
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
о
о
22
Yield: 1.79 g (96%) (1.75 g (94%)), light-yellow solid, mp 265-267 С (258-260 С ); IR
-1
1
(
(
7
KBr): nmax 3281, 1620, 1599, 1516, 1349, 1258, 754 cm ; H NMR (600 MHz, CDCl
s, 2H, CH ), 7.19 (dd, J=8.1, 6.8 Hz, 1H, H6-Q), 7.28-7.38 (m, 4H, H5-Q, H2,4,6-Ar1), 7.35-
.40 (m, 4H, H3,5-Ar1, H7,8-Q), 7.69 (d, J=8.8 Hz, 2H, H2,6-Ar2), 8.43 (d, J=8.8 Hz, 2H,
H3,5-Ar2); C{ H} NMR (150.9 MHz, CDCl
140.0 (C1-Ar2), 135.4 (C1-Ar1), 133.9 (C8a), 131.3 (C6-Ar2), 129.0 (C3-Ar1), 127.9 (C7),
27.8 (C4-Ar1), 126.7 (C2-Ar1), 125.6 (C5), 123.9 (C5-Ar2), 123.5 (C6), 121.5 (C4), 121.2
3
): d 5.72
2
1
3
1
3
): d 159.1 (C2), 147.8 (C4-Ar2), 141.0 (C3),
1
+
(C4a), 115.5 (C8), 47.3 (CH
2
); HRMS (MALDI-TOF) m/z: [M + H] Calcd for C22
H
17
N
2
O
4
3
73.1183; Found 373.1195.
3
-Hydroxy-4-(4-nitrophenyl)-N-(4-methoxybenzyl)quinolin-2-one (4i).
о
Yield: 1.97 g (98%) (1.87 (93%)), tan solid, mp 267-269 С; IR (KBr): nmax 3284, 1621, 1601,
-
1 1
1
514, 1350, 1249, 751 cm ; H NMR (600 MHz, CDCl
CH ), 6.90 (d, J=8.6 Hz, 2H, H3,5-Ar1), 7.19 (dd, J=7.6, 7.5 Hz, 1H, H6-Q), 7.26 (d, J=8.7 Hz,
2H, H2,6-Ar1), 7.28 (d, 1H, J=7.4 Hz, H5-Q), 7.39 (dd, J=8.2, 7.4 Hz, 1H, H7-Q), 7.46 (d, J=8.3
Hz, 1H, H8-Q), 7.68 (d, J=8.5 Hz, 2H, H2,6-Ar2), 8.42 (d, J=8.5 Hz, 2H, H3,5-Ar2); C{ H}
NMR (150.9 MHz, CDCl ): d 159.2 (C4-Ar1), 159.0 (C2), 147.8 (C4-Ar2), 141.1 (C3), 140.0
C1-Ar2), 133.9 (C8a), 131.3 (C6-Ar2), 128.2 (C2-Ar1), 127.8 (C7), 127.5 (C1-Ar1), 125.5
C5), 123.9 (C5-Ar2), 123.5 (C6), 121.3 (C4), 121.2 (C4a), 115.5 (C8), 114.4 (C3-Ar1), 55.3
3
): d 3.80 (s, 3H, OMe), 5.65 (s, 2H,
2
1
3
1
3
(
(
(
+
OMe), 46.8 (CH
2
); HRMS (MALDI-TOF) m/z: [M + H] Calcd for C23
H
19
N
2
O 403.1288;
5
Found 403.1298.
3-Hydroxy-4-(4-cianophenyl)-N-methylquinolin-2-one (4j).
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1
2
3
4
5
6
7
8
9
о
Yield: 1.37 g (99%) (1.34 g (97%)), tan solid, mp 240-242 С; IR (KBr): nmax 3240, 2226, 1628,
1600, 1265, 754 cm ; H NMR (500 MHz, CDCl
Hz, 1H, H6-Q), 7.28 (d, J=7.6 Hz, 1H, H5-Q), 7.47 (d, J=8.2 Hz, 1H, H8-Q), 7.52 (dd, J=8.2,
.0 Hz, 1H, H7-Q), 7.58 (d, J=7.8 Hz, 2H, H2,6-Ar), 7.84 (d, J=7.7 Hz, 2H, H3,5-Ar); C{ H}
NMR (125.7 MHz, CDCl ): d 158.8 (C2-Q), 141.1 (C3-Q), 138.1 (C1-Ar), 134.5 (C8a-Q), 132.4
C3-Ar), 131.0 (C2-Ar), 127.8 (C7-Q), 125.5 (C5-Q), 123.4 (C6-Q), 121.2 (C4a-Q), 121.0 (C4-
Q), 118.6 (CN), 114.5 (C8-Q), 112.2 (C4-Ar), 30.6 (NMe); N NMR (50.6 MHz, CDCl
140.3 (N1); HRMS (MALDI-TOF) m/z: [M + H] Calcd for C17
-
1 1
3
): d 3.93 (s, 3H, NMe), 7.24 (dd, J=7.6, 6.9
1
3
1
7
3
(
1
5
3
): δ
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
H
13
N
2
O
2
277.0972; Found
277.0981.
3
-Hydroxy-4-(4-cianophenyl)-N-benzylquinolin-2-one (4k).
о
Yield: 1.74 g (99%) (1.67 (95%)), white solid, mp 210-211 С; IR (KBr): nmax 3307, 2225, 1708,
1620, 1601, 1259, 754 cm ; H NMR (500 MHz, CDCl
6.8 Hz, 1H, H6-Q), 7.27-7.33 (m, 4H, H5-Q, H2,4,6-Ar1), 7.34-7.43 (m, 4H, H7,8-Q, 3,5-Ar1),
-
1 1
3
): d 5.72 (s, 2H, CH ), 7.19 (dd, J=8.0,
2
13
1
7
.62 (d, J=8.3 Hz, 2H, H2,6-Ar2), 7.86 (d, J=8.3 Hz, 2H, H3,5-Ar2); C{ H} NMR (125.7
MHz, CDCl ): d 159.1 (C2-Q), 141.0 (C3-Q), 138.1 (C1-Ar2), 135.4 (C1-Ar1), 133.9 (C8a-Q),
32.4 (C3-Ar2), 131.0 (C2-Ar2), 130.0 (C3-Ar1), 127.8 (C7-Q), 127.7 (C4-Ar1), 126.6 (C2-
Ar1), 125.6 (C5-Q), 123.5 (C6-Q), 122.0 (C4-Q), 121.3 (C4a-Q), 118.6 (CN), 115.4 (C8-Q),
3
1
1
5
112.2 (C4-Ar2), 47.3 (CH
m/z: [M + H] Calcd for C23 353.1285; Found 353.1299.
2
); N NMR (50.6 MHz, CDCl
3
): δ 151 (N1). HRMS (MALDI-TOF)
+
H
17
N
2
O
2
3
-Hydroxy-4-(4-cianophenyl)-N-(4-methoxybenzyl)quinolin-2-one (4l).
о
Yield: 1.87 g (98%) (1.74 g (91%)), tan solid, mp 241-243 С; IR (KBr): nmax 3188, 2230, 1707,
-
1 1
1609, 1594, 1514, 1279, 1248, 762, 748 cm ; H NMR (500 MHz, CDCl
5.65 (s, 2H, CH ), 6.89 (d, J=8.7 Hz, 2H, H3,5-Ar1), 7.19 (dd, J=7.9, 7.1 Hz, 1H, H6-Q), 7.26
d, J=8.6 Hz, 2H, H2,6-Ar1), 7.27 (d, J=7.2 Hz, 1H, H5-Q), 7.39 (ddd, J=7.9, 7.1, 1.4 Hz, 1H,
H7-Q), 7.46 (d, J=8.0 Hz, 1H, H8-Q), 7.61 (d, J=8.5 Hz, 2H, H2,6-Ar2), 7.85 (d, J=8.5 Hz, 2H,
3
): d 3.80 (s, 3H, OMe),
2
(
1
3
1
H3,5-Ar2); C{ H} NMR (125.7 MHz, CDCl
3
): d 159.2 (C4-Ar1), 159.1 (C2-Q), 141.0 (C3-Q),
38.1 (C4-Ar1), 133.9 (C8a-Q), 132.4 (C3-Ar2), 131.0 (C2-Ar2), 128.2 (C2-Ar1), 127.7 (C7-Q),
27.5 (C1-Ar1), 125.6 (C5-Q), 123.4 (C6-Q), 121.7 (C4-Q), 121.3 (C4a-Q), 118.6 (CN), 115.4
); HRMS (MALDI-TOF) m/z:
1
1
(C8-Q), 114.4 (C3-Ar1), 112.3 (C4-Ar2), 55.3 (OMe), 46.7 (CH
[
2
+
M + Cs] Calcd for C24
H
18
N
2
O Cs 515.0366; Found 515.0380.
3
3
-Hydroxy-4-(3-nitrophenyl)-6-methyl-N-(4-methoxybenzyl)quinolin-2-one (4m).
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0
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
о
Yield: 0.94 g (45%), white solid, mp 245-247 С; IR (KBr): nmax 3251, 1613, 1529, 1513, 1349,
-
1 1
1
248, 804 cm ; H NMR (500 MHz, CDCl
3
): d 2.30 (s, 3H, Me), 3.81 (s, 3H, OMe), 5.64 (s, 2H,
CH ), 6.89 (d, J=8.7 Hz, 2H, H3,5-Ar1), 7.03 (s, 1H, H5-Q), 7.20 (d, J=8.7 Hz, 1H, H7-Q), 7.25
(d, J=8.7 Hz, 2H, H2,6-Ar1), 7.35 (d, J=8.6 Hz, 1H, H8-Q), 7.76 (dd, J=8.8, 7.7 Hz, 1H, H5-
Ar2), 7.82 (d, J=7.7 Hz, 1H, H6-Ar2), 8.36 (s, 1H, H2-Ar2), 8.37 (d, J=8.6 Hz, 1H, H4-Ar2);
C{ H} NMR (125.7 MHz, CDCl ): d 159.1 (C4-Ar1), 158.8 (C2-Q), 148.6 (C3-Ar2), 141.3
C3-Q), 136.4 (C6-Ar2), 134.9 (C1-Ar2), 133.1 (C6-Q), 131.9 (C8a-Q), 129.7 (C5-Ar2), 129.0
C7-Q), 128.1 (C2-Ar1), 127.6 (C1-Ar1), 125.3 (C2-Ar2), 125.2 (C5-Q), 123.2 (C4-Ar2), 121.3
C4a-Q), 120.9 (C4-Q), 115.4 (C8-Q), 114.4 (C3-Ar1), 55.3 (OMe), 46.7 (CH ), 20.9 (C6-Me);
2
13
1
3
(
(
(
2
1
5
+
N NMR (50.6 MHz, CDCl
417.1445; Found 417.1451.
-Chloro-2-oxo-3-(3-nitrophenyl)-N-(4-tolyl)-N-(3-methoxybenzyl)propionamide (5m).
3
): δ 153 (N1), 367 (NO ); HRMS (MALDI-TOF) m/z: [M + H]
2
Calcd for C24
H
21
N
2
O
5
3
-1
1
Yield: 0.52 g (23%), yellow thick oil; IR: nmax 1728, 1651, 1513, 1352, 1250, 833 cm ; H NMR
): d 2.33 (s, 3H, Me), 3.81 (s, 3H, OMe), 4.84 (d, J=11.4 Hz, 2H, NCH
s, 1H, H3), 6.74 (d, J=8.0 Hz, 2H, H2,6-Ar1), 6.80 (d, J=8.4 Hz, 2H, H3,5-Ar2), 7.06 (d, J=7.9
(
(
500 MHz, CDCl
3
2
), 6.04
Hz, 2H, H3,5-Ar1), 7.09 (d, J=8.5 Hz, 2H, H2,6-Ar2), 7.53 (dd, J=8.0, 7.9 Hz, 1H, H5-Ar3),
1
3
1
7.63 (d, J=7.8 Hz, 1H, H6-Ar3), 8.06 (s, 1H, H2-Ar3), 8.21 (d, J=8.1 Hz, 1H, H4-Ar3); C{ H}
NMR (100 MHz, CDCl ): d 189.1 (C2), 164.1 (C1), 159.3 (C4-Ar2), 148.3 (C3-Ar3), 139.0 (C4-
Ar1), 136.1 (C1-Ar3), 136.0 (C1-Ar1), 134.9 (C6-Ar3), 130.2 (C2-Ar2), 129.9 (C3-Ar1), 129.7
C5-Ar3), 128.0 (C2-Ar1), 127.7 (C1-Ar2), 124.1 (C4-Ar3), 123.9 (C2-Ar3), 113.9 (C3-Ar2),
), 21.1 (Me); N NMR (50.6 MHz, CDCl
67.4 (NO ); HRMS (MALDI-TOF) m/z: [M + Cs] Calcd for C24
3
(
6
3
1
5
0.9 (C3), 55.2 (OMe), 52.7 (CH
2
3
): δ 140.9 (N1),
Cs 585.0188;
+
2
H
21ClN
2
O
5
Found 585.0181.
3-Hydroxy-4-(4-cianophenyl)-6-methyl-N-(4-methoxybenzyl)quinolin-2-one (4n).
о
Yield: 0.95 g (48%), white solid, mp 277-279 С; IR (KBr): nmax 3290, 2228, 1609, 1513, 1245,
-
1 1
1036 cm ; H NMR (400 MHz, CDCl
3
): d 2.29 (s, 3H, Me), 3.79 (s, 3H, OMe), 5.62 (s, 2H,
CH ), 6.88 (d, J=8.7 Hz, 2H, H3,5-Ar1), 7.01 (s, 1H, H5-Q), 7.19 (d, J=8.4 Hz, 1H, H7-Q), 7.24
2
(d, J=8.6 Hz, 2H, H2,6-Ar1), 7.33 (d, J=8.4 Hz, 1H, H8-Q), 7.59 (d, J=8.3 Hz, 2H, H2,6-Ar2),
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(
.85 (d, J=8.2 Hz, 2H, H3,5-Ar2); C{ H} NMR (100.6 MHz, CDCl
C2-Q), 141.0 (C3-Q), 138.2 (C1-Ar2), 133.1 (C6-Q), 132.4 (C3-Ar2), 131.9 (C8a-Q), 131.0
(C2-Ar2), 128.9 (C7-Q), 128.1 (C2-Ar1), 127.7 (C1-Ar1), 125.3 (C5-Q), 121.4 (C4-Q), 121.2
C4a-Q), 118.7 (CN), 115.3 (C8-Q), 114.4 (C3-Ar1), 112.2 (C4-Ar2), 55.3 (OMe), 46.7 (CH2),
3
): d 159.1 (C4-Ar1), 158.8
(
+
2
5
0.9 (C6-Me); HRMS (MALDI-TOF) m/z: [M + Cs] Calcd for C25
H
20
N
2
3
O Cs 529.0523; Found
29.0507.
3
-Chloro-2-oxo-3-(4-cianophenyl)-N-(4-tolyl)-N-(3-methoxybenzyl)propionamide (5n).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
1
Yield: 0.58 g (27%), yellow thick oil; IR: nmax 2231, 1732, 1651, 1513, 1249 cm ; H NMR (500
MHz, CDCl ): 2.34 (s, 3H, Me), 3.81 (s, 3H, OMe), 4.83 (d, J=4.2 Hz, 2H, NCH ), 5.98 (s, 1H,
3
2
H3), 6.72 (d, J=8.2 Hz, 2H, H2,6-Ar1), 6.81 (d, J=8.7 Hz, 2H, H3,5-Ar2), 7.05 (d, J=8.1 Hz, 2H,
H3,5-Ar1), 7.08 (d, J=8.7 Hz, 2H, H2,6-Ar2), 7.39 (d, J=8.5 Hz, 2H, H2,6-Ar3), 7.62 (d, J=8.4
): d 188.9 (C2), 164.0 (C1), 159.3 (C4-
Ar2), 138.9 (C1-Ar3), 138.9 (C4-Ar1), 136.2 (C1-Ar1), 132.4 (C3-Ar3), 130.2 (C2-Ar2), 129.9
C3-Ar1), 129.6 (C2-Ar3), 127.9 (C2-Ar1), 127.7 (C1-Ar2), 118.1 (CN), 113.9 (C3-Ar2), 113.2
C4-Ar3), 61.3 (C3), 55.2 (OMe), 52.8 (CH2), 21.1 (Me); HRMS (MALDI-TOF) m/z: [M + Cs]
1
3
1
Hz, 2H, H3,5-Ar3); C{ H} NMR (150.9 MHz, CDCl
3
(
(
+
Calcd for C25
H
21ClN
2
O
3
Cs 565.0290; Found 565.0277.
viridicatol from
Syntheses
of
8
3-hydroxy-4-(3-nitrophenyl)-N-(4-
methoxybenzyl)quinolin-2-one (4f). Method A: Step 1 (Reduction of 4f). To a stirred solution of
4f (0.80 g, 2.0 mmol) in DMF (120 mL) was added a solution of Na (1.39 g, 8 mmol) in
O (120 mL). The mixture was heated at reflux for 4 h. After cooling, diluted with water (500
mL) and kept at room temperature for 10 h was formed precipitate, which filtered off, washed
with water and dried in air to afford of the analytically pure 6a. Step 2 (Diazotization of 6a,
followed by the elimination of nitrogen). To a stirred solution of 6a (0.56 g, 1.5 mmol) in THF
2
S
2
O
4
H
2
(
50 mL) was added diluted with water (1:1) H
2
SO (0.5 mL, ~4.5 mmol), followed by a 2.5 M
aqueous solution of NaNO (0.6 mL, ~6 mmol) was added at 0-5 С and the resulting mixture
4
о
2
stirred at this temperature for 1 h. At the end of this period, a small amount of urea (~6 mg) was
added to the reaction mixture for the decomposition of the excess of nitrous acid, after which the
stirring was continued at room temperature for 5 h. The reaction mixture was kept at room
temperature for a further 6 h, and water (100 mL) was added. The precipitate was filtered,
washed with water, dried in air. The resulting a tan solid corresponded to compound 6b and was
used in the next step without purification. Step 3 (Removal of PMB (p-metoxybenzyl) group). The
compound of 6a (0.49 g, 1.3 mmol) was heated at reflux in a mixture of trifluoroacetic acid (15
mL), anisole (15 mL) and conc. H
2
SO (0.2 mL) for 4 h. The reaction mixture was kept at room
4
temperature for a further 8 h and stirred with ice-cold water/n-hexane (150 mL/150 mL) mixture
for 15 min. The resulting precipitate was filtered, washed with water and hexane and dried in air
to afford of the analytically pure 8. Method B: Step 1 (Removal of PMB group). The conversion
of 4f (0.80 g, 2.0 mmol) in 7a was carried out analogously to the procedure described in Step 3
of Method A for 6b. Step 2. The reduction of 7a (0.42 g, 1.5 mmol) was carried out analogously
to the procedure described in Step 1 of Method A for 4f. Step 3. The process diazotization of 7b
0.28 g, 1.0 mmol) was carried out analogously to the procedure described in Step 2 of Method A
for 6a.
-Hydroxy-4-(3-aminophenyl)-N-(4-methoxybenzyl)quinolin-2-one (6a).
(
3
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
о
Yield 0.64 g (86%), light violet solid, mp 220-221 С; IR (KBr): nmax 3366, 1616, 1600, 1513,
461, 1248, 751 cm ; H NMR (500 MHz, DMSO-d
.59 (s, 2H, NCH ), 6.45 (d, J=7.7 Hz, 1H, H6-Ar2), 6.54 (dd, J=1.9, 1.8 Hz, 1H, H2-Ar2), 6.63
(d, J=7.9 Hz, 1H, H4-Ar2), 6.91 (d, J=8.8 Hz, 2H, H3,5-Ar1), 7.14 (dd, J=7.5, 7.3 Hz, 1H, H6-
Q), 7.15 (dd, J=7.9, 7.7 Hz, 1H, H5-Ar2), 7.22 (d, J=7.4 Hz, 1H, H5-Q), 7.23 (d, J=8.8 Hz, 2H,
H2,6-Ar1), 7.32 (dd, J=8.3, 7.5, 1H, H7-Q), 7.45 (d, J=8.4 Hz, 1H, H8-Q), 9.13 (s, 1H, OH);
C{ H} NMR (125.7 MHz, DMSO-d ): d 158.6 (C2-Q), 158.4 (C4-Ar1), 148.6 (C3-Ar2), 141.3
C3-Q), 134.2 (C1-Ar2), 133.3 (C8a-Q), 128.8 (C5-Ar2), 128.5 (C1-Ar1), 128.0 (C2-Ar1), 126.6
C7-Q), 125.5 (C5-Q), 124.4 (C4-Q), 122.3 (C6-Q), 122.0 (C4a-Q), 117.1 (C6-Ar2), 115.2 (C2-
Ar2), 115.1 (C8-Q), 114.1 (C3-Ar1), 113.2 (C4-Ar2), 55.0 (OMe), 45.0 (CH ); N NMR (50.6
-
1 1
1
5
6
): d 3.72 (s, 3H, OMe), 5.15 (s, 2H, NH ),
2
2
1
3
1
6
(
(
1
5
2
+
MHz, DMSO-d
Cs 505.0523; Found 505.0533.
-Hydroxy-4-(3-hydroxyphenyl)-N-(4-methoxybenzyl)quinolin-2-one (6b).
6
): δ 153 (N1), 60 (NH ); HRMS (MALDI-TOF) m/z: [M + Cs] Calcd for
2
C
23
H
20
N
2
O
3
3
o
o
20
Yield 0.54 g (97%), tan solid, mp 242-143 С (238-242 С ); IR (KBr): nmax 3277, 1614, 1598,
515, 1253, 1031, 1017, 749 cm ; H NMR (500 MHz, DMSO-d
s, 2H, NCH ), 6.75 (s, 1H, H2-Ar2), 6.76 (ddd, J=7.8, 2.1, 1.1 Hz, 1H, H6-Ar2), 6.86 (ddd,
-
1 1
1
(
6
): d 3.72 (s, 3H, OMe), 5.60
2
J=8.2, 2.3, 1.0 Hz, 1H, H4-Ar2), 6.91 (d, J=8.8 Hz, 2H, H3,5-Ar1), 7.13 (ddd, J=8.0, 7.1, 0.8
Hz, 1H, H6-Q), 7.19 (dd, J=8.1, 1.5 Hz, 1H, H5-Q), 7.25 (d, J=8.8 Hz, 2H, H2,6-Ar1), 7.32 (dd,
J=8.1, 7.9 Hz, 1H, H5-Ar2), 7.33 (ddd, J=8.5, 7.0, 1.5, 1H, H7-Q), 7.47 (d, J=8.4 Hz, 1H, H8-
1
3
1
Q), 9.26 (s, 1H, OH-Q), 9.54 (s, 1H, OH-Ar2); C{ H} NMR (125.7 MHz, DMSO-d
6
): d 158.4
C2-Q), 158.4 (C4-Ar1), 157.3 (C3-Ar2), 141.3 (C3-Q), 134.8 (C1-Ar2), 133.4 (C8a-Q), 129.4
C5-Ar2), 128.4 (C1-Ar1), 128.1 (C2-Ar1), 126.7 (C7-Q), 125.3 (C5-Q), 123.7 (C4-Q), 122.4
(
(
(C6-Q), 121.7 (C4a-Q), 120.4 (C6-Ar2), 116.7 (C2-Ar2), 115.1 (C8-Q), 114.7 (C4-Ar2), 114.1
); N NMR (50.6 MHz, DMSO-d
TOF), m/z: [M + H] Calcd for C23 374.1387; Found 374.1388.
1
5
(C3-Ar1), 55.0 (OMe), 45.0 (CH
2
6
): δ 153.1; HRMS (MALDI-
+
H
20NO
4
3
-Hydroxy-4-(3-nitrophenyl)-N-(4-methoxybenzyl)quinolin-2-one (7a).
о
Yield 0.44 g (78%), tan solid, mp 272-274 С; IR (KBr): nmax 3308, 1669, 1575, 1530, 1504,
-
1 1
1347, 1293 cm ; H NMR (500 MHz, DMSO-d6): d 7.05 (d, J=8.0 Hz, 1H, H5-Q), 7.11 (dd,
J=8.1, 6.4, 1.9 Hz, 1H, H6-Q), 7.34-7.41 (m, 2H, H7,8-Q), 7.82-7.85 (m, 2H, H5,6-Ar), 8.18 (dd,
J=1.5, 1.2 Hz, 1H, H2-Ar), 8.32 (ddd, J=6.1, 3.6, 2.9 Hz, 1H, H4-Ar), 9.59 (s, 1H, OH), 12.29 (s,
1
3
1
1
H, NH); C{ H} NMR (100.6 MHz, DMSO-d6): d 158.0 (C2-Q), 148.0 (C3-Ar), 143.0 (C3-
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Q), 136.9 (C6-Ar), 135.4 (C1-Ar), 133.2 (C8a-Q), 130.1 (C5-Ar), 126.7 (C7-Q), 124.7 (C2-Ar),
23.8 (C5-Q), 122.7 (C4-Ar), 122.4 (C6-Q), 121.6 (C4-Q), 120.2 (C4a-Q), 115.4 (C8-Q); N
NMR (50.6 MHz, DMSO-d6): δ 148 (N1), 371 (NO
Calcd for C15 283.0713; Found 283.0711.
1
5
1
+
2
); HRMS (MALDI-TOF) m/z: [M + H]
H
11
N
2
O
4
3
-Hydroxy-4-(3-aminophenyl)-N-(4-methoxybenzyl)quinolin-2-one (7b).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Yield 0.31 g (82%), tan solid, mp 277 С; IR (KBr): nmax 3318, 1654, 1574, 1290, 1227, 752 cm-
о
1
1
;
H NMR (500 MHz, DMSO-d
6
): d 5.13 (s, 2H, NH ), 6.43 (d, J=7.4 Hz, 1H, H6-Ar), 6.52 (s,
1H, H2-Ar1), 6.62 (d, J=8.0 Hz, 1H, H4-Ar), 7.08 (ddd, J=7.2, 7.1, 1.9 Hz, 1H, H6-Q), 7.14 (dd,
J=8.0, 7.5 Hz, 1H, H5-Ar), 7.14 (d, J=7.3 Hz, 1H, H5-Q), 7.28-7.35 (m, 2H, H7,8-Q), 8.97 (s,
H, OH), 12.14 (s, 1H, NH); C{ H} NMR (125.7 MHz, DMSO-d
C3-Ar), 142.0 (C3-Q), 134.2 (C1-Ar), 133.0 (C8a-Q), 128.7 (C5-Ar), 126.3 (C7-Q), 124.8 (C4-
Q), 124.7 (C5-Q), 121.9 (C6-Q), 121.1 (C4a-Q), 117.1 (C6-Ar), 115.2 (C2-Ar), 115.1 (C8-Q),
2
13
1
1
6
): d 159.1 (C2-Q), 148.6
(
1
5
1
13.2 (C4-Ar); N NMR (50.6 MHz, DMSO-d
6
): δ 147 (N1), 60 (NH
2
); HRMS (MALDI-TOF)
+
+
m/z: [M + H] Calcd for C15
H
13
N
2
O
2
253.0972; Found 253.0965; [M + Na] Calcd for
+
C
15
H
12
N
2
O
2
Na 275.0791; Found 275.0782; [M + Cs] Calcd for C15
84.9961.
-Hydroxy-4-(3-aminophenyl)-N-(4-methoxybenzyl)quinolin-2-one (8).
H
12
N
2
2
O Cs 384.9948; Found
3
3
Yield 0.25 (Method A) and 0.25 (Method B) g (77 and 98%), tan solid, mp 268-270 °C (268-271
2
0
o
22
-1 1
°
C , 238-240 C ); IR (KBr): nmax 3240, 1652, 1592, 1395, 1283, 1246 cm ; H NMR (500
MHz, DMSO-d ): d 6.72 (d, J=1.2 Hz, 1H, H2-Ar), 6.73 (d, J=7.5 Hz, 1H, H6-Ar), 6.83 (dd,
J=8.3, 1.5 Hz, 1H, H4-Ar), 7.06-7.13 (m, 2H, H5,6-Q), 7.28-7.37 (m, 3H, H5-Ar, H7,8-Q), 9.10
s, 1H, OH-Q), 9.53 (s, 1H, OH-Ar), 12.18 (s, 1H, NH); C{ H} NMR (125.7 MHz, DMSO-d
d 158.3 (C2-Q), 157.3 (C3-Q), 142.2 (C3-Ar), 134.9 (C1-Ar), 133.1 (C8a-Q), 129.4 (C5-Ar),
26.4 (C7-Q), 124.5 (C5-Q), 124.1 (C4-Q), 122.1 (C6-Q), 120.9 (C4a-Q), 120.4 (C6-Ar), 116.7
(C2-Ar1), 115.2 (C8-Q), 114.6s (C4-Ar); N NMR (50.6 MHz, DMSO-d
(MALDI-TOF) m/z: [M + H] Calcd for C15
Calcd for C15 Cs 385.9788; Found 385.9798.
6
13
1
(
6
):
1
1
5
6
): δ 147.3; HRMS
+
254.0812; Found 254.0820; [M + Cs]+
H
12NO
3
H
11NO
3
ASSOCIATED CONTENT
Supporting information
Experimental procedures and compound characterization data including 1D and 2D NMR
spectra for most of compounds, 1D and 2D NMR spectra for most of compounds, computational
details for 3a, 5a, X-ray crystal data (CIF) for 3e, 4h, 5a, 5b and 5c. This material is available
free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
Vakhid A. Mamedov
*
E-mail: mamedov@iopc.ru.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The work was partially supported by the Russian Science Foundation (grant No. 14-23-00073-p).
REFERENCES
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(
1) (a) Angibaud, P. R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny, Y. A.; Muller, P.;
Poncelet, V. S.; End, D. W. Synthesis Routes Towards the Farnesyl Protein Transferase Inhibitor
ZARNESTRA. Eur. J. Org. Chem. 2004, 479-486. (b) Cappelli, A.; Mohr, G. la P.; Gallelli, A.;
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