One-pot three-component reaction of 3-(polyfluoroacyl)chromones with active methylene compounds and ammonium acetate: regioselective synthesis of novel RF-containing nicotinic acid derivatives

Article abstract of DOI:10.1016/j.tet.2008.01.076

Reactions of 3-(polyfluoroacyl)chromones with acetoacetamide and ethyl acetoacetate in the presence of ammonium acetate proceed at the C-2 atom of the chromone system with pyrone ring-opening and subsequent cyclization to 5-salicyloyl-2-methyl-6-(trifluoromethyl)nicotinamides, ethyl 5-salicyloyl-2-methyl-6-(trifluoromethyl)nicotinates, and ethyl 5-hydroxy-2-methyl-5-(polyfluoroalkyl)-5H-chromeno[4,3-b]pyridine-3-carboxylates. Similar reaction with β-aminocrotononitrile gave 5-hydroxy-2-methyl-5-(polyfluoroalkyl)-5H-chromeno[4,3-b]pyridine-3-carbonitriles.

Full text of DOI:10.1016/j.tet.2008.01.076

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2997e3004
www.elsevier.com/locate/tet
One-pot three-component reaction of 3-(polyfluoroacyl)chromones with
active methylene compounds and ammonium acetate: regioselective
synthesis of novel RF-containing nicotinic acid derivatives
a
b
Vyacheslav Ya. Sosnovskikh a, , Roman A. Irgashev , Mikhail I. Kodess
*
a Department of Chemistry, Ural State University, 620083 Ekaterinburg, Russian Federation
b Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 620041 Ekaterinburg, Russian Federation
Received 5 October 2007; received in revised form 3 January 2008; accepted 17 January 2008
Available online 25 January 2008
Abstract
Reactions of 3-(polyfluoroacyl)chromones with acetoacetamide and ethyl acetoacetate in the presence of ammonium acetate proceed at the
C-2 atom of the chromone system with pyrone ring-opening and subsequent cyclization to 5-salicyloyl-2-methyl-6-(trifluoromethyl)nicotina-
mides, ethyl 5-salicyloyl-2-methyl-6-(trifluoromethyl)nicotinates, and ethyl 5-hydroxy-2-methyl-5-(polyfluoroalkyl)-5H-chromeno[4,3-b]pyri-
dine-3-carboxylates. Similar reaction with b-aminocrotononitrile gave 5-hydroxy-2-methyl-5-(polyfluoroalkyl)-5H-chromeno[4,3-b]pyridine-
3-carbonitriles.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Three-component reactions; 3-(Polyfluoroacyl)chromones; Active methylene compounds; Ammonium acetate; Nicotinic acid derivatives
1. Introduction
of these compounds with such dinucleophiles as hydrazines and
hydroxylamine start predominantly from the attack of the
unsubstituted C-2 atom (1,4-addition) and are accompanied
by pyrone ring-opening to form the b-dicarbonyl intermediate
capable of regioselective intramolecular heterocyclizations.
Along with this route, the initial attack can proceed at the
3-RFCO group as well (1,2-addition), which does not exclude
the variant of recyclization due to the intramolecular Michael
reaction and the subsequent ring-opening with cleavage of the
O(1)eC(2) bond.2
As a continuation of our studies on the synthetic potential
of 3-(polyfluoroacyl)chromones, and owing to the increasing
importance of fluorine-containing heterocycles in biology,
pharmacology, and industrial applications,3 we decided to in-
vestigate their reactions with acetoacetamide and acetoacetic
ester in the presence of ammonium acetate, as well as with ethyl
b-aminocrotonate and b-aminocrotononitrile in order to de-
velop a simple synthesis of novel RF-containing nicotinic acid
derivatives. It has been shown previously that 3-formylchro-
mone 1 readily reacts with active methylene compounds and
ammonia to give pyridine derivatives 2e4, depending on the
The introduction of a polyfluoroacyl group into the 3-posi-
tion of the chromone system changes crucially the reactivity
of the pyrone ring with respect to nucleophiles and stipulates
the broad synthetic potential of 3-(polyfluoroacyl)chromones.
The diversity of properties of these compounds is due to the
fact that, being actually highly reactive geminally activated
pushepull alkenes with a good leaving group at the b-carbon
atom, they acquire the ability to undergo additional transforma-
tions related to opening and recyclization of the g-pyrone ring.
Strangely enough, but these compounds have long remained out
of sight of chemists engaged in organic synthesis, and their
systematic study has started only in recent years. Nevertheless,
it is already clear that 3-(polyfluoroacyl)chromones are valu-
able substrates for the synthesis of diverse fluorine-containing
heterocycles with a potential biological activity.1 The reactions
* Corresponding author. Fax: þ7 343 261 59 78.
E-mail address: vyacheslav.sosnovskikh@usu.ru (V.Ya. Sosnovskikh).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.076

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V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 2997e3004
reaction conditions and the nature of dinucleophiles (Scheme
1).4 The formation of compounds 2 and 3 can proceed via
both the 1,4- and 1,2-addition of the central carbon atom of
the active methylene molecule due to chemical equivalence
of the CHO group and C-2 atom of 1. However, chromenopyr-
idine 4 certainly is the product of the primary 1,4-addition
followed by the pyrone ring-opening, attack of the NH2 group
to the carbonyl bound with the aromatic cycle, and ring-closure
involving the phenolic hydroxyl and CHO group.
b-aminocrotononitrile and ethyl b-aminocrotonates, affords
2- and 4-(trifluoromethyl)pyridines.5bef These compounds
were also obtained from the reaction of trifluoromethylated
a,b-unsaturated ketones and b-diketones with N-silyl-1-
azaallyl anions,5g by Hantzsch’s dihydropyridine synthesis5h,i
and Suzuki cross-coupling.5j
2. Results and discussion
Herein, we wish to report the successful regioselective syn-
thesis of novel RF-containing nicotinic acid derivatives from 3-
(polyfluoroacyl)chromones 5 and enamines arising from active
methylene compounds. We have reasoned that when chromones
5 were coupled with these 1,3-C,N-dinucleophiles, the similar
electrophilic character of the C-2 atom and the carbonyl carbon
of 3-polyfluoroacyl group would lead to a mixture of regioiso-
meric products. However, when chromones 5aec were treated
in refluxing ethanol with acetoacetamide in the presence
of ammonium acetate, a smooth reaction took place and
2-methyl-5-salicyloyl-6-(trifluoromethyl)nicotinamides 6aec
were obtained in moderate yields (Scheme 2). Compounds
6aec are precipitated from the reaction solution and analyt-
ically pure products can be isolated by simple filtration. In
the light of the present interest in fluoroheteroaromatics as phar-
maceutical intermediates,3 this novel entry to fluorinated nico-
tinamides is noteworthy.
The first step of the reaction consists apparently of an attack
at the C-2 atom of chromones by the internal carbon of b-ami-
nocrotonamide (in general, this atom is more nucleophilic than
the primary amino group in acidic conditions) with concomitant
opening of the pyrone ring (1,4-addition, intermediate A), and
finally, the intramolecular attack at the CF3CO group by the
amino group leads to 6-CF3-pyridines 6aec. The driving force
of the dehydration is probably due to the formation of an
Me
CO2R
O
O
N
O
Me
CHO
CO2R
NH2
OH
4
1
1) AcCH2CO2R
2) NH3
AcCH2CONH2
OH
OH
O
O
CO2R
Me
COMe
N
N
H
O
2
3
Scheme 1.
On the other hand, remarkable progress has been made in
the development of new and efficient methods for synthesis
of polyfluoroalkylated pyridine derivatives using fluorinated
building blocks. 2,6-Diaryl-4-(trifluoromethyl)pyridines have
recently been synthesized by the reaction of enamines, pre-
pared from substituted acetophenones and morpholine, with
trifluoromethylated b-diketones in the presence of ammonium
acetate.5a The condensation of CF3-containing a,b-unsaturated
ketones and b-diketones with primary enamines, such as
O
O
O
CF3
O
CF3
R
R
CONH2
Me
R
i
CF3
O
X
1,4-AN
CONH2
1,2-AN
O
5a-c
O
HN
OH
B
A
H2N
Me
X
H
H
Me
O
R
O
CF3
O
R
O
CF3
N
CONH2
N
O
CONH2
Me
N
R
OH
CF3
Me
CONH2
6''
6'
6a-c
Reaction conditions (i): AcCH2CONH2, AcONH4, EtOH
Chromone
R
Product
6a
Yield (%)
Mp (°C)
252–253
242–243
228–229
5a
5b
5c
H
46
50
48
Me
Cl
6b
6c
Scheme 2.

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 2997e3004
2999
aromatic pyridine derivative. The alternative cyclization of
A involving the amino group and the carbonyl carbon atom con-
nected to the benzene ring to give chromeno[4,3-b]pyridines 60
does not occur. Note that for the initial attack of the CF3CO
group by the internal atom of b-aminocrotonamide (1,2-addi-
tion) the reaction through the ring-closure/ring-opening
sequence would result in isomeric 4-CF3-pyridines 600.
(CDCl3, DMSO-d6) due to H-4 with a coupling constant value
3J¼8.5 Hz. Such coupling value is characteristic for pyridine
protons H-3 and H-4 and much higher than that for H-2 and
H-3 (4e6 Hz).6 These pyridines are likely the result of the in
situ detrifluoroacetylation of chromenopyridines 8 (Scheme
3). The mechanism probably follows a course similar to that
described in Scheme 2. Thus, ethyl b-aminocrotonate in the re-
action with 5aec turned out to be less selective reactant, whose
amino group attacks both carbonyls in intermediate A with
equal success.
Asexpected, regioselectivityof the nucleophilic attackby the
NH2 group of intermediate A on the two carbonyl carbon atoms
will depend on the electronic and steric effects of the RF group.
In fact, the reaction of chromones 5deh with acetoacetic ester
under the same reaction conditions afforded chromeno[4,3-b]-
pyridine-3-carboxylates 8deh in 26e69% isolated yields. In
this reaction, the attack of the NH2 group is mainly directed to
the carbonyl at the aromatic ring, due to which the RFCO group
remains free and can participate in the formation of cyclic semi-
ketal form 8. In the case of 5feh, the improved regioselectivity
is probably due to the steric bulk of the H(CF2)2 group and the
lower electrophilicity of the carbonyl carbon atom connected
to this group (Scheme 4).
All signals in the 1H and 13C NMR spectra of compound 6a
were assigned on the basis of 2D HSQC and HMBC experi-
ments. For choosing between structures 6 and 600, the former
one was decisively favored by the fact that the H-4 proton is
3
bound due to the JC,H coupling constants with the carbon
atoms C-2, C-6, CO, and NCO (in the case of 600, the latter con-
stant could not appear). In addition, the C-4 atom has the upfield
chemical shift (134.85 ppm), which is not characteristic of
atoms directly bound to the pyridine nitrogen atom. Thus,
the regiochemistry was determined and higher reactivity of a
CF3CO than ArCO of intermediate A toward the amino group
was shown.
It has been reported previously that pyridine 2 (R¼Me),
prepared by condensation of 3-formylchromone 1 with methyl
acetoacetate followed by treatment with ammonia, is isomeric
to pyridine 4 from the reaction of 1 with methyl b-aminocroto-
nate.4a However, in our case, the reactions of chromones 5aec
with both ethyl acetoacetate in the presence of ammonium
acetate and ethyl b-aminocrotonate gave the same result. In all
cases, mixtures of approximately equal amounts of compounds
7aec and 8aec were obtained (Scheme 3). The products aris-
ing from chromones 5a,b were separated by recrystallization
from methanol or hexane/ether, and the isolated yield of 7a,b
and 8b was 12e20%. The structures of products 7b and 8b
were established by their elemental and spectral analyses, in-
cluding 2D HSQC and HMBC experiments. Note that isomers
7b and 8b can easily be distinguished by the 19F NMR spectra
in which the singlet of the CF3 group is observed at 99.65 and
78.84 ppm (DMSO-d6, HFB), respectively. Besides compounds
7 and 8, a small amount of pyridines 9 has also been detected
by 1H NMR spectroscopy, although we have been unable to iso-
Similarly, the reaction of chromones 5ceg with b-amino-
crotononitrile in refluxing ethanol in the presence of acetic
acid gave chromenopyridines 10ceg. Only one regioisomer
has been obtained in this two-component condensation, albeit
in only 23e42% yields. As it was expected, the lowest yield of
the products was obtained for CF3-substituted chromones 5c,d,
whose reaction is less unambiguous (Scheme 5). In the cases
of compounds 8f,g and 10f,g, the attachment of the (CF2)2H
1
group to a chiral center is clearly supported by the H NMR
spectra, in which the terminal hydrogen atom of this group
(d 6.78e6.82 ppm) is split into a triplet of doublets of doublets
2
3
with JH,F¼51.6e51.8 Hz and JH,F¼7.4e7.9, 5.3e5.6 Hz
instead of the usual triplet of triplets.
Finally, we have found that dimedone enamine arising from
dimedone and ammonium acetate in refluxing ethanol reacted
with chromones 5a,b,eeg and gave 2-(2-hydroxyaryl)-7,7-di-
methyl-7,8-dihydroquinolin-5(6H)-ones 11a,b in low yields
(22e25%). The reaction includes the nucleophilic 1,4-addition
of the internal carbon atom with concomitant opening of the
pyrone ring and subsequent intramolecular cyclization with
the participation of the NH2 and ArCO groups followed by
depolyfluoroacylation (Scheme 6).
1
late them in pure form. The H NMR spectra of compounds
9aec revealed two doublets at d 7.76e7.81 ppm (CDCl3) or
8.15e8.17 ppm (DMSO-d6) due to H-5 and 8.35e8.40 ppm
O
O
R
CF3
O
Note that unsubstituted chromone under the same reaction
conditions gave compound 11a in only 7% yield. A character-
istic feature of the 1H NMR spectra of 11a,b is the appearance
of two AB doublets (J¼8.6 Hz) at d 8.2 and 8.3 ppm for the pyr-
idine H-3 and H-4 protons and a singlet at d 13.7e14.0 ppm
corresponding to the OH proton resonance.
5a-c
i or ii
Me
H
CF3
O
R
O
CO2Et
CO2Et
Me
N
N
R
R
N
H
+
+
OH
CF3
Me
CO2Et
O
O
3. Conclusion
7a-c
8a-c
9a-c
Reaction conditions (i): AcCH2CO2Et, AcONH4, EtOH;
(ii) MeC(NH2)C=CHCO2Et, AcOH, EtOH;
R = H (a), Me (b), Cl (c)
In conclusion, we have shown that 3-(polyfluoroacyl)chro-
mones, readily available from the condensation products of
2-hydroxyacetophenones with RFCO2Et and diethoxymethyl
Scheme 3.

3000
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 2997e3004
Me
CO2Et
O
O
N
RF
AcCH2CO2Et
OH
RF
R
R
AcONH4, EtOH
O
O
5d-h
8d-h
Chromone
R
RF
Product
Yield (%)
Mp (°C)
5d
5e
5f
7-MeO
H
CF3
8d
8e
8f
31
26
69
34
50
213–214
184–185
180–181
218–219
208–209
CF2H
H
(CF2)2H
(CF2)2H
(CF2)2H
5g
5h
6-Me
7-MeO
8g
8h
Scheme 4.
Me
CN
O
O
N
Me
CN
RF
NH2
OH
RF
R
R
AcOH, EtOH
O
O
5c-g
10c-g
Chromone
R
RF
Product
Yield (%)
Mp (°C)
5c
5d
5e
5f
6-Cl
CF3
10c
10d
10e
10f
23
24
41
42
36
192–194
236–238
212–214
193–194
220–222
7-MeO
H
CF3
CF2H
(CF2)2H
(CF2)2H
H
5g
6-Me
10g
Scheme 5.
the ready accessibility of the starting materials, cheap reagents,
and operational simplicity.
O
Me Me
O
O
Me
Me
R
R
RF
O
O
N
H
4. Experimental
AcONH4, EtOH
O
O
5a,b,e-g
4.1. General
R = H (11a), Me (11b)
Scheme 6.
1H (400 MHz), 13C (100 MHz), and 19F (376 MHz) NMR
spectra were recorded on a Bruker DRX-400 spectrometer in
DMSO-d6 with TMS and C6F6 as internal standards, respec-
tively. Assignment of chemical shifts was based on standard
2D NMR techniques (1He13C HSQC and HMBC). IR spectra
were recorded on a PerkineElmer Spectrum BX-II instrument
as KBr discs. Elemental analyses were performed at the Micro-
analysis Services of the Institute of Organic Synthesis, Ural
Branch, Russian Academy of Sciences. Melting points are
acetate,1 reacted with active methylene compounds and ammo-
nium acetate giving either densely substituted pyridines or
chromeno[4,3-b]pyridines, depending on the nature of 1,3-C,N-
dinucleophile and the length of the polyfluoroalkyl group. By
proper choice of these parameters the RF-containing pyridines
could be selectively obtained in moderate yields. In addition,
the method appears to be useful and convenient in terms of

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 2997e3004
3001
uncorrected. All solvents used were dried and distilled as per
standard procedures. The starting chromones 5aeh were pre-
pared according to described procedure.1
13.0 mmol) in ethanol (5 mL) was refluxed for 4 h. The resultant
reactionmixturewascooledanddilutedwithwater. Theprecipitate
that formed was filtered and washed with cooled aqueous ethanol
(1:1) to give a mixture of 7e9.
Procedure B. A solution of chromone 5 (1 mmol), acetic acid
(240 mg, 4.0 mmol), and ethyl b-aminocrotonate (260 mg,
2.0 mmol) in ethanol (5 mL) was refluxed for 0.5e4 h. After
the removal of solvent under reduced pressure, the residue was
purified by recrystallization from benzene, toluene or methanol
to give a mixture of 7e9.
4.2. General procedure for pyridines 6aec
A mixture of chromone 5 (1.0 mmol), acetoacetamide
(250 mg, 2.5 mmol), and ammonium acetate (1.0 g, 13.0 mmol)
inethanol(5 mL)wasrefluxedfor4 h.Thenthesolventwasevap-
orated at heating to half of its initial volume and then cooled. The
precipitate formed was filtered and washed with aqueous ethanol
(1:1) to give pyridines 6 as colorless crystals.
4.3.1. Ethyl 5-salicyloyl-2-methyl-6-(trifluoromethyl)-
nicotinate (7a)
4.2.1. 5-Salicyloyl-2-methyl-6-(trifluoromethyl)nicotin-
amide (6a)
This compound was prepared according to procedure A from
a mixture of composition 7a/8a/9¼35:50:15 by recrystalliza-
tion from hexane/ether (10:1). Yield 18%, mp 103e104 ꢀC;
1H NMR (400 MHz, CDCl3) d 1.40 (t, 3H, Me, J¼7.1 Hz),
2.98 (s, 3H, Me), 4.42 (q, 2H, CH2, J¼7.1 Hz), 6.86 (ddd, 1H,
Yield 46%, mp 252e253 ꢀC; IR (KBr) 3399, 3316, 3171,
1696, 1623, 1607, 1576, 1488 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6) d 2.67 (s, 3H, Me), 6.95e7.00 (m, 2H, H-30,
H-50), 7.54e7.60 (m, 2H, H-40, H-60), 7.82 (br s, 1H, NH),
7.98 (s, 1H, H-4), 8.12 (br s, 1H, NH), 10.83 (s, 1H, OH);
13C NMR (100 MHz, DMSO-d6) d 22.5 (Me), 117.7 (C-30),
4
H-50, 3J¼8.0, 7.2 Hz, J¼1.0 Hz), 7.09 (dd, 1H, H-60,
4
3J¼8.0 Hz, J¼1.6 Hz), 7.10 (dd, 1H, H-30, 3J¼8.5 Hz,
3
4
4J¼1.0 Hz), 7.56 (ddd, 1H, H-40, J¼8.5, 7.2 Hz, J¼1.6 Hz),
8.25 (s, 1H, H-4), 11.65 (s, 1H, OH); 19F NMR (376 MHz,
CDCl3, HFB) d 97.92 (s, CF3). Anal. Calcd for C17H14F3NO4:
C, 57.79; H, 3.99; N, 3.96. Found: C, 57.71; H, 4.06; N, 3.90.
1
119.5 (C-50), 121.1 (q, CF3, JC,F¼275.4 Hz), 121.4 (C-10),
3
131.79 (C-40), 133.1 (q, C-5, JC,F¼1.2 Hz), 134.6 (C-3),
2
134.9 (C-4), 136.8 (C-60), 141.4 (q, C-6, JC,F¼33.8 Hz),
156.5 (C-2), 160.0 (C-20), 167.8 (NCO), 194.5 (CO). Anal.
Calcd for C15H11F3N2O3: C, 55.56; H, 3.42; N, 8.64. Found:
C, 55.40; H, 3.42; N, 8.40.
4.3.2. Ethyl 5-hydroxy-2-methyl-5-(trifluoromethyl)-5H-
chromeno[4,3-b]pyridine-3-carboxylate (8a) and ethyl 6-
(20-hydroxyphenyl)-2-methylnicotinate (9a)
4.2.2. 5-(20-Hydroxy-50-methylbenzoyl)-2-methyl-6-
(trifluoromethyl)nicotinamide (6b)
These compounds were not obtained in pure form. 1H NMR
(400 MHz, CDCl3) Compound 8a: d 1.41 (t, 3H, Me,
J¼7.1 Hz), 2.90 (s, 3H, Me), 4.38 (q, 2H, CH2, J¼7.1 Hz),
5.0e5.2 (br s, 1H, OH), 7.01 (dd, 1H, H-7, 3J¼8.2 Hz,
Yield 50%, mp 242e243 ꢀC; IR (KBr) 3380, 3317, 3180,
1699, 1630, 1598, 1586, 1482 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6) d 2.23 (s, 3H, Me), 2.67 (s, 3H, Me), 6.87 (d,
3
4J¼0.9 Hz), 7.10 (m, 1H, H-9), 7.35 (ddd, 1H, H-8, J¼8.2,
4
3
1H, H-30, J¼8.4 Hz), 7.34 (br d, 1H, H-60, J¼1.6 Hz), 7.39
(dd, 1H, H-40, 4J¼8.4 Hz, 3J¼2.2 Hz), 7.81 (s, 1H, NH),
7.94 (s, 1H, H-6), 8.10 (s, 1H, NH), 10.61 (s, 1H, OH); 13C
NMR (100 MHz, DMSO-d6) d 19.8, 22.5, 117.6, 121.0,
121.1 (q, CF3, 275.3 Hz), 128.3, 131.2, 133.2, 134.5, 134.8,
137.8, 141.4 (q, CeCF3, 33.7 Hz), 156.4, 158.0, 167.8,
194.5. Anal. Calcd for C16H13F3N2O3: C, 56.81; H, 3.87; N,
8.28. Found: C, 56.73; H, 3.67; N, 8.22.
7.4 Hz, 4J¼1.7 Hz), 8.25 (dd, 1H, H-10, 3J¼7.8 Hz,
1
4J¼1.7 Hz), 8.32 (s, 1H, H-4); H NMR (400 MHz, DMSO-
d6) Compound 9a: d 1.33 (t, 3H, Me, J¼7.1 Hz), 2.82 (s, 3H,
Me), 4.31e4.40 (m, 2H, OCH2), 6.93e7.00 (m, 2H, H-30,
3
4
H-50), 7.37 (ddd, 1H, H-40, J¼8.5, 7.0 Hz, J¼1.6 Hz), 8.06
(dd, 1H, H-60, 3J¼8.2 Hz, 4J¼1.6 Hz), 8.17 (d, 1H, H-5,
3J¼8.5 Hz), 8.36 (d, 1H, H-4, 3J¼8.5 Hz), 14.08 (s, 1H, OH).
4.2.3. 5-(50-Chloro-20-hydroxybenzoyl)-2-methyl-6-(trifluoro-
methyl)nicotinamide (6c)
4.3.3. Ethyl 5-(20-hydroxy-50-methylbenzoyl)-2-methyl-
6-(trifluoromethyl)nicotinate (7b)
This compound was prepared according to procedure B from
a mixture of composition 7b/8b¼76:24 by recrystallization
from methanol. Yield 20%, mp 140e142 ꢀC; IR (KBr) 1732,
1638, 1620, 1592, 1555, 1487 cmꢁ1 1H NMR (400 MHz,
;
Yield 48%, mp 228e229 ꢀC; IR (KBr) 3386, 3318, 3177,
1698, 1624, 1602, 1571, 1467 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6) d 2.67 (s, 3H, Me), 6.95 (d, 1H, H-30,
4
3
4J¼8.8 Hz), 7.58 (dd, 1H, H-40, J¼8.8 Hz, J¼2.8 Hz), 7.62
(d, 1H, H-60, 3J¼2.8 Hz), 7.81 (s, 1H, NH), 7.96 (s, 1H,
H-4), 8.09 (s, 1H, NH), 10.86 (s, 1H, OH); 19F NMR
(376 MHz, DMSO-d6, HFB) d 99.89 (s, CF3). Anal. Calcd
for C15H10ClF3N2O3: C, 50.23; H, 2.81; N, 7.81. Found: C,
50.16; H, 2.68; N, 8.10.
DMSO-d6) d 1.32 (t, 3H, Me, J¼7.1 Hz), 2.24 (s, 3H, Me),
2.84 (s, 3H, Me), 4.35 (q, 2H, CH2, J¼7.1 Hz), 6.87 (d, 1H,
3
3
4
H-30, J¼8.4 Hz), 7.38 (dd, 1H, H-40, J¼8.5 Hz, J¼2.3 Hz),
4
7.43 (d, 1H, H-60, J¼2.2 Hz), 8.32 (s, 1H, H-4), 10.57 (s,
1
1H, OH); H NMR (400 MHz, CDCl3) d 1.41 (t, 3H, Me,
J¼7.1 Hz), 2.20 (s, 3H, Me), 2.99 (s, 3H, Me), 4.43 (q, 2H,
4
4.3. General procedures for pyridines 7e9
CH2, J¼7.1 Hz), 6.82 (br d, 1H, H-60, J¼1.5 Hz), 7.00 (d,
3
1H, H-30, J¼8.5 Hz), 7.37 (dd, 1H, H-40, 3J¼8.5 Hz,
Procedure A. A mixture of chromone 5 (1.0 mmol), ethyl
acetoacetate (320 mg, 2.5 mmol), and ammonium acetate (1.0 g,
4J¼2.0 Hz), 8.24 (s, 1H, H-4), 11.50 (s, 1H, OH); 19F NMR
(376 MHz, DMSO-d6, HFB) d 99.65 (s, CF3); 19F NMR

3002
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 2997e3004
(376 MHz, CDCl3, HFB) d 97.92 (s, CF3); 13C NMR
(100 MHz, DMSO-d6) d 13.8 (CH2Me), 19.7 (ArMe), 23.9
(PyMe), 61.8 (OCH2), 117.6 (C-30), 120.9 (q, CF3,
1JC,F¼275.7 Hz), 121.2 (C-10), 124.4 (C-3), 128.3 (C-50),
carboxylate (8c), and ethyl 5-(50-chloro-20-hydroxybenzoyl)-
2-methyl-4-(trifluoromethyl)nicotinate (9c)
A mixture of composition 7c/8c/9c¼4:5:1 was obtained ac-
1
cording to procedures A and B. H NMR (400 MHz, CDCl3)
3
131.0 (C-60), 133.9 (q, C-5, JC,F¼1.2 Hz), 137.7 (C-40),
Compound 7c: d 1.43 (t, 3H, Me, J¼7.1 Hz), 2.99 (s, 3H, Me),
2
3
137.9 (C-4), 143.1 (q, C-6, JC,F¼34.1 Hz), 157.8 (C-20),
4.44 (q, 2H, CH2, J¼7.1 Hz), 7.01 (d, 1H, H-30, J¼8.8 Hz),
159.0 (C-2), 164.6 (COO), 193.5 (CO); 13C NMR (100 MHz,
CDCl3) d 14.2 (CH2Me), 20.3 (ArMe), 24.7 (PyMe), 62.2
(OCH2), 118.5 (C-30), 119.0 (C-10), 120.7 (q, CF3,
1JC,F¼276.1 Hz), 127.8 (C-3), 128.7 (C-50), 130.1 (C-60),
132.2 (C-5), 138.8 (C-40), 139.0 (C-4), 145.3 (q, C-6,
2JC,F¼35.0 Hz), 161.2 (C-20), 161.4 (C-2), 164.7 (COO),
197.9 (CO). Anal. Calcd for C18H16F3NO4: C, 58.86; H, 4.39;
N, 3.81. Found: C, 58.94; H, 4.12; N, 3.70.
7.03 (d, 1H, H-60, J¼2.6 Hz), 7.51 (dd, 1H, H-40, J¼8.7 Hz,
4J¼2.6 Hz), 8.24 (s, 1H, H-4), 11.57 (s, 1H, OH); Compound
8c: d 1.42 (t, 3H, Me, J¼7.1 Hz), 2.92 (s, 3H, Me), 4.41 (q, 2H,
CH2, J¼7.1 Hz), 4.6e5.4 (br s, 1H, OH), 7.07 (d, 1H, H-7,
3
3
3J¼8.9 Hz), 7.34 (dd, 1H, H-8, J¼8.8 Hz, J¼2.6 Hz), 8.37
3
4
4
(d, 1H, H-10, J¼2.6 Hz), 8.45 (s, 1H, H-4); Compound 9c:
d 1.43 (t, 3H, Me, J¼7.1 Hz), 2.91 (s, 3H, Me), 4.42 (q, 2H,
3
CH2, J¼7.1 Hz), 7.00 (d, 1H, H-30, J¼8.9 Hz), 7.27 (dd, 1H,
3
4
4
H-40, J¼8.9 Hz, J¼2.5 Hz), 7.75 (d, 1H, H-60, J¼2.5 Hz),
4.3.4. Ethyl 5-hydroxy-2,9-dimethyl-5-(trifluoromethyl)-5H-
chromeno[4,3-b]pyridine-3-carboxylate (8b)
7.76 (d, 1H, H-5, 3J¼8.5 Hz), 8.40 (d, 1H, H-4, 3J¼8.5 Hz).
This compound was prepared according to procedure A from
a mixture of composition 7b/8b/9b¼55:35:10 by recrystalliza-
tion from hexane/ether (1:1). Yield 12%, mp 184e185 ꢀC;
4.3.7. Ethyl 5-hydroxy-8-methoxy-2-methyl-5-(trifluoro-
methyl)-5H-chromeno[4,3-b]pyridine-3-carboxylate (8d)
This compound was prepared according to procedure A.
Yield 31%, mp 213e214 ꢀC; IR (KBr) 1723, 1653, 1620,
IR (KBr) 1729, 1638, 1621, 1589, 1560 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6) d 1.36 (t, 3H, Me, J¼7.1 Hz), 2.36 (s,
1588, 1559, 1512 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
;
3H, Me), 2.86 (s, 3H, Me), 4.38 (br q, 2H, CH2, J¼7.0 Hz),
d 1.34 (t, 3H, Me, J¼7.1 Hz), 2.83 (s, 3H, Me), 3.84 (s, 3H,
3
3
7.05 (d, 1H, H-7, J¼8.3 Hz), 7.31 (dd, 1H, H-8, J¼8.4 Hz,
MeO), 4.34 (dq, 1H, CHH, J¼10.8, 7.1 Hz), 4.37 (dq, 1H,
4J¼2.0 Hz), 8.09 (d, 1H, H-10, 4J¼2.3 Hz), 8.32 (s, 1H, H-4),
CHH, J¼10.8, 7.1 Hz), 6.71 (d, 1H, H-7, J¼2.4 Hz), 6.79
4
1
9.48 (s, 1H, OH); H NMR (400 MHz, CDCl3) d 1.42 (t, 3H,
(dd, 1H, H-9, 3J¼8.8 Hz, 4J¼2.4 Hz), 8.17 (d, 1H, H-10,
3J¼8.8 Hz), 8.26 (s, 1H, H-4), 9.53 (s, 1H, OH). Anal. Calcd
for C18H16F3NO5$0.25H2O: C, 55.75; H, 4.29; N, 3.61.
Found: C, 55.57; H, 4.15; N, 3.58.
Me, J¼7.1 Hz), 2.35 (s, 3H, Me), 2.90 (s, 3H, Me), 4.38 (q,
2H, CH2, J¼7.1 Hz), 4.8e5.2 (br s, 1H, OH), 6.92 (d, 1H,
3
3
4
H-7, J¼8.3 Hz), 7.16 (dd, 1H, H-8, J¼8.3 Hz, J¼1.9 Hz),
8.04 (br d, 1H, H-10, 4J¼1.7 Hz), 8.33 (s, 1H, H-4); 19F
NMR (376 MHz, DMSO-d6, HFB) d 78.84 (s, CF3); 13C
NMR (100 MHz, DMSO-d6) d 14.0 (CH2Me), 20.2 (ArMe),
4.3.8. Ethyl 5-(difluoromethyl)-5-hydroxy-2-methyl-5H-
chromeno[4,3-b]pyridine-3-carboxylate (8e)
2
24.7 (PyMe), 61.3 (OCH2), 95.7 (q, C-5, JC,F¼32.5 Hz),
This compound was prepared according to procedure B.
Yield 26%, mp 184e185 ꢀC; IR (KBr) 3094, 1729, 1612,
116.5 (C-7), 118.1 (C-10a), 119.9 (C-3), 122.38 (q, CF3,
1JC,F¼289.0 Hz), 124.7 (C-10), 128.2 (q, C-4a, 3JC,F¼1.2 Hz),
1602, 1588, 1557, 1490 cmꢁ1; H NMR (400 MHz, DMSO-
1
4
131.9 (C-9), 133.8 (C-8), 137.1 (q, C-4, JC,F¼1.2 Hz), 148.7
d6) d 1.35 (t, 3H, Me, J¼7.1 Hz), 2.84 (s, 3H, Me), 4.35 (dq,
(C-10b), 150.8 (C-6a), 161.3 (C-2), 165.1 (COO). Anal. Calcd
for C18H16F3NO4: C, 58.86; H, 4.39; N, 3.81. Found: C, 58.52;
H, 4.38; N, 3.89.
1H, CHH, J¼10.8, 7.1 Hz), 4.38 (dq, 1H, CHH, J¼10.8,
2
7.1 Hz), 6.31 (t, 1H, CF2H, JH,F¼54.4 Hz), 7.08 (dd, 1H, H-
7, 3J¼8.2 Hz, 4J¼0.9 Hz), 7.17 (td, 1H, H-9, 3J¼7.7 Hz,
3
4
4J¼1.0 Hz), 7.47 (ddd, 1H, H-8, J¼8.3, 7.3 Hz, J¼1.7 Hz),
3
4
4.3.5. Ethyl 6-(20-hydroxy-50-methylphenyl)-2-methyl-
nicotinate (9b)
8.26 (dd, 1H, H-10, J¼7.8 Hz, J¼1.7 Hz), 8.29 (s, 1H, H-
4), 8.78 (br s, 1H, OH). Anal. Calcd for C17H15F2NO4: C,
60.89; H, 4.51; N, 4.18. Found: C, 60.58; H, 4.32; N, 3.98.
1
This compound was not obtained in pure form. H NMR
(400 MHz, DMSO-d6) d 1.35 (t, 3H, Me, J¼7.1 Hz), 2.31 (s,
3H, Me), 2.81 (s, 3H, Me), 4.35e4.40 (q, 2H, CH2,
J¼7.1 Hz), 6.86 (d, 1H, H-30, 3J¼8.4 Hz), 7.18 (dd, 1H,
4.4. General procedure for pyridines 8feh
3
4
4
H-40, J¼8.5 Hz, J¼2.0 Hz), 7.86 (d, 1H, H-60, J¼2.0 Hz),
A mixture of chromone 5feh (1 mmol), ethyl acetoacetate
(320 mg, 2.5 mmol), and ammonium acetate (1.0 g, 13.0 mmol)
in ethanol (5 mL) was refluxed for 4 h. Then the solvent was
evaporated to half of its initial volume and then cooled. The
precipitate formed was filtered and washed with cooled aqueous
ethanol (1:1) to give pyridines 8feh as colorless crystals.
3
4
8.15 (d, 1H, H-5, J¼8.5 Hz), 8.35 (d, 1H, H-4, J¼8.5 Hz),
1
13.84 (s, 1H, OH); H NMR (400 MHz, CDCl3) d 1.43 (t,
3H, Me, J¼7.1 Hz), 2.35 (s, 3H, Me), 2.91 (s, 3H, Me), 4.41
3
(q, 2H, CH2, J¼7.1 Hz), 6.97 (d, 1H, H-30, J¼8.5 Hz), 7.17
3
(br d, 1H, H-40, J¼8.5 Hz), 7.60 (br s, 1H, H-60), 7.81 (d,
3
3
1H, H-5, J¼8.5 Hz), 8.37 (d, 1H, H-4, J¼8.5 Hz).
4.4.1. Ethyl 5-hydroxy-2-methyl-5-(1,1,2,2-tetrafluoroethyl)-
5H-chromeno[4,3-b]pyridine-3-carboxylate (8f)
4.3.6. Ethyl 5-(50-chloro-20-hydroxybenzoyl)-2-methyl-6-
(trifluoromethyl)nicotinate (7c), ethyl 9-chloro-5-hydroxy-2-
methyl-5-(trifluoromethyl)-5H-chromeno[4,3-b]pyridine-3-
Yield 69%, mp 180e181 ꢀC; IR (KBr) 3430, 1730, 1588,
1
1558 cmꢁ1; H NMR (400 MHz, DMSO-d6) d 1.36 (t, 3H,

V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 2997e3004
3003
Me, J¼7.1 Hz), 2.86 (s, 3H, Me), 4.37 (br q, 2H, CH2,
8.32 (d, 1H, H-10, 4J¼2.6 Hz). Anal. Calcd for C15H8ClF3N2O2:
2
J¼7.0 Hz), 6.82 (tdd, 1H, CF2CF2H, JH,F¼51.8 Hz,
C, 52.88; H, 2.37; N, 8.22. Found: C, 52.89; H, 2.25; N, 8.12.
3
3JH,F¼7.4, 5.3 Hz), 7.09 (d, 1H, H-7, J¼8.1 Hz), 7.19 (t, 1H,
3
3
H-9, J¼7.5 Hz), 7.49 (t, 1H, H-8, J¼7.6 Hz), 8.26 (d, 1H,
4.5.2. 5-Hydroxy-8-methoxy-2-methyl-5-(trifluoromethyl)-
5H-chromeno[4,3-b]pyridine-3-carbonitrile (10d)
3
H-10, J¼7.6 Hz), 8.30 (s, 1H, H-4), 9.45 (s, 1H, OH). Anal.
Calcd for C18H15F4NO4: C, 56.11; H, 3.92; N, 3.64. Found:
C, 56.23; H, 3.88; N, 3.71.
Yield 24%, mp 236e238 ꢀC; IR (KBr) 3441, 3082, 2232, 1621,
1586, 1514 cmꢁ1;1H NMR (400 MHz, CDCl3)d2.83 (s, 3H, Me),
3.87 (s, 3H, MeO), 4.01 (br s, 1H, OH), 6.58 (d, 1H, H-7,
4J¼2.4 Hz), 6.75 (dd, 1H, H-9, 3J¼8.8 Hz, 4J¼2.4 Hz), 8.06 (s,
1H, H-4), 8.24 (d, 1H, H-10, 3J¼8.8 Hz); 13C NMR (100 MHz,
DMSO-d6)d23.6(Me), 55.8(OMe), 96.2(q,C-5, 2JC,F¼33.3 Hz),
101.3 (C-7), 106.2 (C-3), 110.3 (C-9), 111.1 (C-10a), 116.8 (CN),
118.6 (C-4a), 122.2 (q, CF3, 1JC,F¼289.8 Hz), 126.5 (C-10), 139.6
(C-4), 149.5 (C-10b), 154.8 (C-6a), 163.3 (C-2), 163.9 (C-8).
Anal. Calcd for C16H11F3N2O3: C, 57.15; H, 3.30; N, 8.33. Found:
C, 56.91; H, 3.28; N, 8.33.
4.4.2. Ethyl 5-hydroxy-2,9-dimethyl-5-(1,1,2,2-tetrafluoro-
ethyl)-5H-chromeno[4,3-b]pyridine-3-carboxylate (8g)
Yield 34%, mp 218e219 ꢀC; IR (KBr) 3438, 1728, 1590,
1
1561 cmꢁ1; H NMR (400 MHz, DMSO-d6) d 1.35 (t, 3H,
Me, J¼7.1 Hz), 2.35 (s, 3H, Me), 2.85 (s, 3H, Me), 4.35 (dq,
1H, CHH, J¼10.9, 7.1 Hz), 4.38 (dq, 1H, CHH, J¼10.9,
2
3
7.1 Hz), 6.80 (tdd, 1H, CF2CF2H, JH,F¼51.8 Hz, JH,F¼7.9,
3
5.2 Hz), 6.98 (d, 1H, H-7, J¼8.4 Hz), 7.29 (dd, 1H, H-8,
4
4
3J¼8.4 Hz, J¼2.0 Hz), 8.06 (d, 1H, H-10, J¼2.0 Hz), 8.29
(d, 1H, H-4, J¼1.5 Hz), 9.38 (s, 1H, OH); 13C NMR
(100 MHz, DMSO-d6) d 14.0 (CH2Me), 20.3 (ArMe), 24.8
4.5.3. 5-(Difluoromethyl)-5-hydroxy-2-methyl-5H-chromeno
[4,3-b]pyridine-3-carbonitrile (10e)
2
(PyMe), 61.3 (OCH2), 97.3 (dd, C-5, JC,F¼29.8, 26.0 Hz),
Yield 41%, mp 212e214 ꢀC; IR (KBr) 3421, 3093, 2232,
1
2
1
108.6 (tt, CF2H, JC,F¼250.3, JC,F¼29.0 Hz), 113.6 (tt, CF2,
1589, 1556 cmꢁ1; H NMR (400 MHz, DMSO-d6) d 2.78 (s,
1JC,F¼260.6, JC,F¼22.8 Hz), 116.5 (C-7), 118.5 (C-10a),
3H, Me), 6.36 (t, 1H, CF2H, JH,F¼54.2 Hz), 7.11 (dd, 1H,
2
2
3
4
3
120.4 (C-4a), 124.1 (C-3), 124.6 (C-10), 131.7 (C-9), 133.6
H-7, J¼8.2 Hz, J¼0.9 Hz), 7.19 (td, 1H, H-9, J¼7.6 Hz,
4
3
4
(C-8), 137.8 (d, C-4, JC,F¼3.1 Hz), 149.1 (C-10b), 151.1
4J¼1.1 Hz), 7.50 (ddd, 1H, H-8, J¼8.3, 7.3 Hz, J¼1.7 Hz),
8.25 (dd, 1H, H-10, 3J¼7.8 Hz, 4J¼1.7 Hz), 8.33 (s, 1H, H-4),
8.82 (s, 1H, OH); 19F NMR (376 MHz, DMSO-d6, HFB)
(C-6a), 161.0 (C-2), 165.2 (COO). Anal. Calcd for
C19H17F4NO4: C, 57.15; H, 4.29; N, 3.51. Found: C, 57.17;
H, 4.26; N, 3.83.
2
2
d 27.67 (dd, CFFH, JF,F¼281.6 Hz, JF,H¼54.2 Hz), 31.95
(dd, CFFH, JF,F¼281.6 Hz, JF,H¼54.2 Hz); 13C NMR
(100 MHz, DMSO-d6) d 23.6(Me), 96.1(t, C-5, 2JC,F¼23.5 Hz),
107.1(C-3), 113.6(t, CF2H, 1JC,F¼249.7 Hz), 116.8(CN), 117.0
(C-7), 118.4 (C-10a), 121.2 (C-4a), 122.5 (C-9), 124.9 (C-10),
133.5 (C-8); 139.3 (C-4), 149.3 (C-10b), 153.4 (C-6a), 162.4
(C-2). Anal. Calcd for C15H10F2N2O2: C, 62.50; H, 3.50; N,
9.72. Found: C, 62.49; H, 3.40; N, 9.74.
2
2
4.4.3. Ethyl 5-hydroxy-8-methoxy-2-methyl-5-(1,1,2,2-tetra-
fluoroethyl)-5H-chromeno[4,3-b]pyridine-3-
carboxylate (8h)
Yield 50%, mp 208e209 ꢀC; IR (KBr) 3445, 1718, 1622,
1
1586, 1514 cmꢁ1; H NMR (400 MHz, DMSO-d6) d 1.34 (t,
3H, Me, J¼7.1 Hz), 2.83 (s, 3H, Me), 3.83 (s, 3H, OMe),
4.34 (dq, 1H, CHH, J¼11.0, 7.1 Hz), 4.37 (dq, 1H, CHH,
J¼11.0, 7.1 Hz), 6.64 (d, 1H, H-7, 4J¼2.4 Hz), 6.77 (dd,
4.5.4. 5-Hydroxy-2-methyl-5-(1,1,2,2-tetrafluoroethyl)-5H-
chromeno[4,3-b]pyridine-3-carbonitrile (10f)
3
4
1H, H-9, J¼8.7 Hz, J¼2.4 Hz), 6.80 (br tt, 1H, CF2CF2H,
3
2JH,F¼51.6 Hz, JH,F¼6.5 Hz), 8.14 (d, 1H, H-10, 3J¼
Yield 42%, mp 193e194 ꢀC; IR (KBr) 3384, 3264, 3081,
8.7 Hz), 8.24 (d, 1H, H-4, J¼1.5 Hz), 9.40 (s, 1H, OH).
Anal. Calcd for C19H17F4NO5: C, 54.94; H, 4.13; N, 3.37.
Found: C, 54.73; H, 3.91; N, 3.36.
2233, 1613, 1601, 1587, 1554, 1493 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6) d 2.80 (s, 3H, Me), 6.81 (tdd, 1H,
2
3
CF2CF2H, JH,F¼51.6 Hz, JH,F¼7.7, 5.4 Hz), 7.10 (d, 1H,
H-7, 3J¼8.2 Hz), 7.20 (ddd, 1H, H-9, 3J¼7.8, 7.3 Hz,
3
4
4.5. General procedure for pyridines 10ceg
4J¼1.0 Hz), 7.52 (ddd, 1H, H-8, J¼8.2, 7.3 Hz, J¼1.7 Hz),
8.23 (dd, 1H, H-10, 3J¼7.8 Hz, 4J¼1.6 Hz), 8.32 (d, 1H, H-4,
J¼1.1 Hz), 9.54 (s, 1H, OH). Anal. Calcd for C16H10F4N2O2:
C, 56.81; H, 2.98; N, 8.28. Found: C, 56.75; H, 2.84; N, 8.12.
Asolutionofchromones5ceg(1 mmol), acetic acid(240 mg,
4.0 mmol), and b-aminocrotononitrile (165 mg, 2.0 mmol) in
ethanol (5 mL) was refluxed for 0.5e4 h. After the removal of
solvent under reduced pressure, the residue was purified by
recrystallization from benzene or toluene to give pyridines
10ceg as colorless crystals.
4.5.5. 5-Hydroxy-2,9-dimethyl-5-(1,1,2,2-tetrafluoroethyl)-
5H-chromeno[4,3-b]pyridine-3-carbonitrile (10g)
Yield 36%, mp 220e222 ꢀC; IR (KBr) 3416, 3086, 2232,
1
1614, 1592, 1556, 1496 cmꢁ1; H NMR (400 MHz, DMSO-
d6) d 2.34 (s, 3H, Me-9), 2.77 (s, 3H, Me-2), 6.78 (tdd, 1H,
4.5.1. 9-Chloro-5-hydroxy-2-methyl-5-(trifluoromethyl)-5H-
chromeno[4,3-b]pyridine-3-carbonitrile (10c)
2
3
CF2CF2H, JH,F¼51.6 Hz, JH,F¼7.6, 5.6 Hz), 6.97 (d, 1H,
3
3
4
Yield 23%, mp 192e194 ꢀC; IR (KBr) 3417, 3098, 2237,
H-7, J¼8.4 Hz), 7.31 (dd, 1H, H-8, J¼8.4 Hz, J¼2.0 Hz),
1
4
1589, 1550, 1482 cmꢁ1; H NMR (400 MHz, CDCl3) d 2.87
8.01 (br d, 1H, H-10, J¼1.5 Hz), 8.27 (s, 1H, H-4), 9.57
(s, 3H, Me), 4.30 (br s, 1H, OH), 7.03 (d, 1H, H-7, 3J¼8.7 Hz),
(br s, 1H, OH). Anal. Calcd for C17H12F4N2O2: C, 57.96; H,
3.43; N, 7.95. Found: C, 57.67; H, 3.49; N, 7.62.
3
4
7.40 (dd, 1H, H-8, J¼8.7 Hz, J¼2.6 Hz), 8.14 (s, 1H, H-4),

3004
V.Ya. Sosnovskikh et al. / Tetrahedron 64 (2008) 2997e3004
4.5.6. 2-(20-Hydroxyphenyl)-7,7-dimethyl-7,8-dihydro-
quinolin-5(6H)-one (11a)
2707e2718; (c) Sosnovskikh, V. Ya.; Irgashev, R. A. Heteroat. Chem.
2006, 17, 99e103; (d) Sosnovskikh, V. Ya.; Irgashev, R. A. Izv. Akad.
Nauk, Ser. Khim. 2006, 2208e2209 (Russ. Chem. Bull., Int. Ed. 2006,
55, 2294e2295); (e) Sosnovskikh, V. Ya.; Irgashev, R. A.; Khalymbadzha,
I. A.; Slepukhin, P. A. Tetrahedron Lett. 2007, 48, 6297e6300.
This compound was prepared according to procedure A from
chromones 5a,e,f, dimedone, and ammonium acetate. Yield
22e25%, mp 142e143 ꢀC; IR (KBr) 1686, 1585, 1562, 1507,
2. (a) Sosnovskikh, V. Ya.; Moshkin, V. S.; Irgashev, R. A. Tetrahedron Lett.
2006, 47, 8543e8546; (b) Sosnovskikh, V. Ya.; Irgashev, R. A.; Moshkin,
V. S.; Kodess, M. I. Presented in part at the 18th International Symposium
on Fluorine Chemistry; Bremen, August 2006; p 308.
1
1472 cmꢁ1; H NMR (DMSO-d6) d 1.08 (s, 6H, 2Me), 2.60
(s, 2H, CH2-6), 3.09 (s, 2H, CH2-8), 6.94e6.98 (m, 2H, H-30,
3
4
H-50), 7.39 (ddd, 1H, H-40, J¼8.3, 7.2 Hz, J¼1.6 Hz), 8.08
3. (a) Organofluorine Compounds in Medicinal Chemistry and Biomedical
Applications; Filler, R., Kobayashi, Y., Yagupolskii, L. M., Eds.; Elsevier:
Amsterdam, 1993; (b) Hiyama, T. Organofluorine Compounds: Chemistry
and Application; Springer: Berlin, 2000.
(dd, 1H, H-60, 3J¼8.5 Hz, 4J¼1.6 Hz), 8.22 (d, 1H, H-3,
3J¼8.6 Hz), 8.31 (d, 1H, H-4, J¼8.6 Hz), 13.98 (s, 1H, OH).
3
Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found:
C, 76.23; H, 6.47; N, 5.34.
4. (a) Haas, G.; Stanton, J. L.; von Sprecher, A.; Wenk, P. J. Heterocycl.
Chem. 1981, 18, 607e612; (b) Ryabukhin, S. V.; Plaskon, A. S.; Voloch-
nyuk, D. M.; Tolmachev, A. A. Synlett 2004, 2287e2290; (c) Heber, D.
Synthesis 1978, 691e692; (d) Abdel-Rahman, A. H.; Hammouda,
M. A. A.; El-Desoky, S. I. Heteroat. Chem. 2005, 16, 20e27; (e) Nohara,
A.; Ishiguro, T.; Sanno, Y. Tetrahedron Lett. 1974, 1183e1186; (f)
Coutinho, D. L. M.; Fernandes, P. S. Indian J. Chem. 1992, 31B, 573e
577; (g) Ghosh, C. K.; Khan, S. Synthesis 1981, 903; (h) Ghosh, C. K.;
Ray, A.; Patra, A. J. Heterocycl. Chem. 2001, 38, 1459e1463; (i) Ghosh,
C. K. Heterocycles 2004, 63, 2875e2898.
4.5.7. 2-(20-Hydroxy-50-methylphenyl)-7,7-dimethyl-7,8-
dihydroquinolin-5(6H)-one (11b)
This compound was prepared according to procedure A from
chromones 5b,g, dimedone, and ammonium acetate. Yield 24%,
mp 193e194 ꢀC. IR (KBr) 1686, 1618, 1582, 1563, 1492,
1455 cmꢁ1; 1H NMR (DMSO-d6) d 1.07 (s, 6H, 2Me), 2.30 (s,
3H, Me), 2.60 (s, 2H, CH2-6), 3.08 (s, 2H, CH2-8), 6.87 (d, 1H,
5. (a) Funabiki, K.; Isomura, A.; Yamaguchi, Y.; Hashimoto, W.; Matsunaga,
K.; Shibata, K.; Matsui, M. J. Chem. Soc., Perkin Trans. 1 2001, 2578e
2582; (b) Katsuyama, I.; Ogawa, S.; Yamaguchi, Y.; Funabiki, K.; Matsui,
M.; Muramatsu, H.; Shibata, K. Synthesis 1997, 1321e1324; (c)
Katsuyama, I.; Funabiki, K.; Matsui, M.; Muramatsu, H.; Shibata, K.
Synlett 1997, 591e592; (d) Cocco, M. T.; Congiu, C.; Onnis, V. J. Hetero-
cycl. Chem. 1995, 32, 543e545; (e) Katsuyama, I.; Ogawa, S.; Nakamura,
H.; Yamaguchi, Y.; Funabiki, K.; Matsui, M.; Muramatsu, H.; Shibata, K.
Heterocycles 1998, 48, 779e785; (f) Okada, E.; Kinomura, T.;
Higashiyama, Y.; Takeuchi, H.; Hojo, M. Heterocycles 1997, 46, 129e132;
(g) Konakahara, T.; Hojahmat, M.; Tamura, S. J. Chem. Soc., Perkin Trans.
3
4
H-30), 7.20 (dd, 1H, H-40, J¼8.3 Hz, J¼1.8 Hz), 7.89 (d, 1H,
H-60, 4J¼1.8 Hz), 8.21 (d, 1H, H-3, 3J¼8.6 Hz), 8.30 (d, 1H, H-
4, 3J¼8.6 Hz), 13.72 (s, 1H, OH). Anal. Calcd for C18H19NO2:
C, 76.84; H, 6.81; N, 4.98. Found: C, 76.64; H, 6.74; N, 4.87.
Acknowledgements
This work was financially supported by the RFBR (Grant
06-03-32388).
1
1999, 2803e2806; (h) Katsuyama, I.; Funabiki, K.; Matsui, M.;
Muramatsu, H.; Shibata, K. Heterocycles 2006, 68, 2087e2096; (i) Lee, L.
F. Eur. Pat. Appl.EP0133612, 1985;Chem. Abstr. 1986, 104, 19514;(j)Xiong,
W.-N.; Yang, C.-G.; Jiang, B. Bioorg. Med. Chem. 2001, 9, 1773e1780.
6. Al-Mousawi, S.; Abdelkhalik, M. M.; John, E.; Elnagdi, M. H. J. Hetero-
cycl. Chem. 2003, 40, 689e695.
References and notes
1. (a) Sosnovskikh, V. Ya.; Irgashev, R. A. Synlett 2005, 1164e1166; (b)
Sosnovskikh, V. Ya.; Irgashev, R. A.; Barabanov, M. A. Synthesis 2006,