Synthesis of new polyfluoroalkyl-containing pyrones, pyridones and pyrido[1,2-a]benzazoles from fluorinated β-alkoxyenones

Article abstract of DOI:10.1055/s-2007-990891

Fluorinated enones were reacted with thiazoles, imidazoles, benzimidazoles and benzthiazoles bearing methylene groups activated by electron-withdrawing substituents. The reactions start with a nucleophilic attack of the methylene carbon on the β-position of the enones. If the starting methylene compound contains a thiazole ring, pyrones or pyridones were formed due to participation of the ester or nitrile groups. In other cases, imidazo-, benzimidazo-or benzthiazo-pyridines were obtained by participation of the nitrogen atom of the corresponding azole rings. In addition to the final products, some primary products were isolated or proved as intermediates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990891

PAPER
3797
Synthesis of New Polyfluoroalkyl-Containing Pyrones, Pyridones and
Pyrido[1,2-a]benzazoles from Fluorinated b-Alkoxyenones
P
olyfluoroalkyl-Co
a
ntaining
P
t
yrones,
a
Pyridones
land Py
i
ridoben
y
zazoles a A. Tolmachova,a Igor I. Gerus,*a Sergey I. Vdovenko,a Günter Haufe,*b Yuriy A. Kirzhnerc
a
b
c
Institute of Bioorganic Chemistry and Petrochemistry NASU, Murmanskaya 1, 03660 Kiev-94, Ukraine
Fax +38(044)5732552; E-mail: igerus@hotmail.com
Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40, 48149 Münster, Germany
Fax +49(251)8339772; E-mail: haufe@uni-muenster.de
Enamine Ltd, A. Matrosova 23, 01103 Kiev, Ukraine
Fax +38(044)5373253; E-mail: nmr@enamine.net
Received 5 July 2007; revised 18 September 2007
heterocycles such as pyrimidines,12 imidazopyridines,13
pyrazoles and isoxazoles.14
Abstract: Fluorinated enones were reacted with thiazoles, imida-
zoles, benzimidazoles and benzthiazoles bearing methylene groups
activated by electron-withdrawing substituents. The reactions start
with a nucleophilic attack of the methylene carbon on the b-position
of the enones. If the starting methylene compound contains a thi-
azole ring, pyrones or pyridones were formed due to participation
of the ester or nitrile groups. In other cases, imidazo-, benzimidazo-
or benzthiazo-pyridines were obtained by participation of the nitro-
gen atom of the corresponding azole rings. In addition to the final
products, some primary products were isolated or proved as inter-
mediates.
Recently, we described an efficient synthesis of 3-acyl-
amino-6-polyfluoroalkyl-2H-pyran-2-ones 5,15 by con-
densation of b-alkoxyvinyl polyfluoroalkyl ketones
(enones) 3 and N-acylglycines 1 and its application in
Diels–Alder reactions.16
As the first step of the reaction, we supposed the forma-
tion of intermediate oxazolones 2 from N-acylglycines 1
and acetic anhydride (Scheme 1). The oxazolones 2 have
an active endocyclic methylene group, which subsequent-
ly undergoes a C–C coupling reaction with the enones 3.
However, we did not observe any reasonable quantity of
intermediate oxazolones 4 in the reaction mixtures by 19F
NMR spectroscopy. In a continuation of our research on
the synthesis of heterocyclic compounds, we have reacted
the enones 3 with a range of active methylene compounds,
such as various azoles bearing an exocyclic methylene
group at position 2, activated by an electron-withdrawing
group (EWG).
Key words: enones, heterocycles, pyridine, 2H-pyran-2-ones,
polyfluoroalkyl group
The introduction of a polyfluoroalkyl group into organic
molecules often confers significant and useful changes in
their chemical and physical properties. Therefore, meth-
ods for the synthesis of polyfluoromethylated compounds
have received considerable interest in recent years.1 Py-
ridines, pyridones and pyrones are basic structural motifs
found in numerous natural products having interesting
properties for medicinal and agricultural applications.
Molecules equipped with these scaffolds are known to ex-
hibit diverse pharmacological activities as neuropeptide
Y1 receptor antagonists,2 muscle relaxants,3 as antitu-
mor,4 antifungal,5 and antiviral6 agents, as free radical
scavengers,7 hypotensive8 and cardiotropic9 substances,
and as inhibitors of voltage-dependent K+ channels.10
RF(O)C
OEt
NHCOR
OH
NHCOR
O
3
Ac2O
O
RF
O
5
1
N
3
N
RF(O)C
Although direct polyfluoroalkylation is the most attrac-
tive and powerful tool with which to construct fluorinated
compounds, polyfluoroalkyl-containing building blocks
are often used as accessible and convenient starting mate-
rials. We systematically investigated the synthetic poten-
tial of readily available b-alkoxyvinyl polyfluoroalkyl
ketones 3, that may be considered as synthetic equivalents
of polyfluoroacylacetaldehyde.11 Numerous examples
demonstrated the versatile synthetic applications of
enones 3 in the synthesis of polyfluoroalkyl-containing
R
O
O
R
O
O
2
4
R = Alk, Ar
RF = CF3, CF2Cl, C3F7
Scheme 1
Reactions of thiazole 6 with enones 3a–c without a sol-
vent, at room temperature, gave products 7 in good to high
yields as a result of acylvinylation of the active methylene
group (Scheme 2).
Products 7a–c can exist in several tautomeric forms and
we elucidated their structure by IR and NMR spectrosco-
py (Table 1 and Table 2). Thus, in the 1H NMR spectra of
SYNTHESIS 2007, No. 24, pp 3797–3806
Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990891; Art ID: T10207SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7

3798
N. A. Tolmachova et al.
PAPER
CORF
OEt
The reaction of 1,3-thiazol-2-ylacetonitriles 10a and 10b,
bearing a nitrile instead of the ester group in thiazole 6,
with enones 3a–c at room temperature in acetic acid gave
pyridines 14 in moderate to high yields (Scheme 3).
S
N
COOEt
S
3a–c
r.t.
N
Me
Me
O
H
6
N
7a–c
CN
S
N
3a–c
neat, r.t.; or
AcOH, r.t.
S
N
CORF
R
R
RF
S
N
S
N
RF
10a,b
11
HO
OEt
Ac2O, 80 °C
O
Me
Me
NuH
O
O
S
N
RF
9a–c
8
Nu
N
+
R
NH
CORF
S
N
EtO
3, 7, 8
a
b
c
13c
RF CF3 CF2Cl C3F7
R
S
N
12
RF
Scheme 2
N
R
HO
NuH = EtOH, H2O
14 a–d
the products 7, characteristic doublets of the vinyl protons
at d = 8.4 and 6.4 ppm with trans-vicinal coupling con-
stants of 15–16 Hz and broad singlets arising from the NH
protons at d = 13.0–14.0 ppm were observed and the posi-
tion of the hydrogen atom at the nitrogen was confirmed
by NOE experiments for compound 7b (Figure 1).
10
a
b
R
Me Ph
11, 14
a
b
c
d
RF CF3 CF2Cl C3F7 CF3
R
Me Me Me Ph
H
COCF2Cl
Scheme 3
H
S
N
H
According to the 19F NMR spectra, the reaction mixtures
contain 85–95% of the products 14. The signals of poly-
fluoroalkyl groups of a main contaminant (5–15%) ap-
peared at lower field. In the case of the reaction of the
perfluoropropyl enone 3c, we isolated the main contami-
nant (15% of the reaction mixture) by column chromato-
graphy. This compound was fully characterized by
spectroscopic methods as the pyridine 13c. Hence, we be-
lieve that the corresponding pyridines 13a,b,d are also
present in the product mixtures of the other reactions. The
formation of the products 14 and 13 can be explained by
competing nucleophilic addition of water or ethanol to the
nitrile group, respectively. In contrast to the previous re-
actions of thiazole 6, where compounds 7 were isolated,
intermediates 11 were not detected by 19F NMR spectros-
copy in the reactions of thiazolylacetonitriles 10a or 10b
with enones 3a–c without a solvent at room temperature.
The lability of intermediates 11, compared to products 7,
is due to the higher reactivity of the nitrile group in hetero-
cyclizations.18
OEt
H3C
O
H
7b
Figure 1 NOE-experiments for compound 7b
Furthermore, in the IR spectra of products 7, a broad ab-
sorption band of an intramolecular hydrogen bond was
observed at 3670–2984 cm–1. The data indicate that com-
pounds 7 exist in tautomeric forms (Scheme 2), with an
intramolecular hydrogen bond between the NH and C=O
groups. A similar structure was suggested previously for
a number of 2-thiazolylacetic esters.17 We believe that, in
contrast to intermediate oxazolones 4, the intramolecular
hydrogen bond sufficiently stabilizes compounds 7 to en-
able its separation and characterization.
Products 7 were cyclized to pyrones 9 by heating in acetic
anhydride. Initially, compound 7 tautomerizes to interme-
diate 8, followed by reaction of the enol and the ester
groups with elimination of ethanol (Scheme 2). The struc-
ture of the synthesized pyrones 9 was confirmed by ele-
mental analysis, IR and NMR spectroscopy (Tables 1 and
Table 2). In the 1H NMR spectra of compounds 9, charac-
teristic doublets of the protons at positions 5 and 4 of the
pyrone ring at d = 8.5 and 6.9 ppm, respectively, with a
cis-vicinal coupling constant of 6–7 Hz were observed.
Also in the IR spectra of products 9, an intense absorption
band of the carbonyl group was observed at 1672–1744
cm–1.
The isolated products 13c and 14a–d gave satisfactory el-
emental analyses and spectroscopic data (IR, 1H, 19F and
13C NMR) consistent with the assigned structures. For ex-
ample, the IR spectra of products 13 and 14 did not show
a nitrile absorption band near 2200 cm–1, but compound
14 had a broad absorption band in the region 3450–3200
cm–1. The NMR spectral data of the products 13c and 14c
are very similar, allowing us to assign the structure of
Synthesis 2007, No. 24, 3797–3806 © Thieme Stuttgart · New York

PAPER
Polyfluoroalkyl-Containing Pyrones, Pyridones and Pyridobenzazoles
3799
EWG
EWG
compounds 14 as 2-hydroxypyridines rather than pyridin-
2-ones in solution.
N
N
N
3a–c
i or ii
N
H
In contrast to the results of the reactions of 1,3-thiazol-2-
ylacetonitriles 10 with enones 3, the reaction between imi-
dazole 16 and enone 3a in hexamethylphosphoramide
(HMPA) at 100 °C after 12 hours gave the product 19 as
a result of cyclization by participation of the endocyclic
nitrogen atom and the COCF3 group, whereas the nitrile
group remained untouched (Scheme 4). The structure of
compound 19 was established on the basis of its NMR and
IR spectroscopic data. In the IR spectrum, the nitrile ab-
sorption band at around 2200 cm–1 was still present.
Under milder reaction conditions (in HMPA at r.t.), imi-
dazole 16 gave intermediate compound 17, whose struc-
ture was found to be similar to that of products 7.
Compound 17 was not stable at elevated temperature (see
its broad melting-point range, Table 1), but cyclized to
imidazopyridine 19 (indicated by TLC).
F
23a–i
20a–d
R
3a–c
10 °C, MeCN
i or ii
H
N
H
N
EWG
EWG
N
N
H
RF
CORF
OH
22a–i
21a–i
(i) 110 °C, toluene (RF = CF3), or (ii) 120 °C, HMPA (RF = CF2Cl, C3F7)
20
a
b
c
d
EWG CN COOMe COPh CONHBn
21–23
EWG CN COPh COOMe CONHBn CN
RF
CF3 CF3 CF3 CF3 CF2Cl CF2Cl C3F7 C3F7
a
b
c
d
e
f
h
i
H
N
H
N
CN
CN
COPh CN COPh
3a
HMPA, r.t.
N
N
H
Me
Me
Scheme 5
COCF3
CN
16
17
HMPA, 100 °C
reflux in HMPA for one hour (assessed by TLC and 19F
NMR). The isolated products 21–23 have satisfactory
H
CN
N
N
N
1
elemental analyses and spectroscopic data (IR, H, 13C
and 19F NMR), which are consistent with the assigned
structures.
Me
N
Me
HO
F3C
CF3
Insertion of an electron-withdrawing substituent (COCF3)
in the a-position of the enone 3a, enhances its reactivity
and the bistrifluoroacetyl compound 24 reacted not only
with benzimidazoles 20a and 20b but also with the sul-
fone 25, which was unreactive towards enone 3a in boil-
ing toluene. Initially, 19F NMR spectra of the reaction
mixtures showed that compounds 26a–c were formed.
However, we only succeeded in isolating product 26b,
which is stabilized by two intramolecular hydrogen
bonds. Its structure was confirmed by X-ray crystal struc-
ture analysis (Figure 2). The reaction of 20a, 20b and 25
with compound 24 under forcing conditions (HMPA,
100 °C) gave the products 23a, 23c and 27 as a result of
elimination of trifluoroacetic acid (Scheme 6).
19
18
Scheme 4
In order to support our assumption of a specific role for
the imidazole ring in the formation of pyridoimidazole 19
via intermediates 17 and 18, we treated the benzimida-
zoles 20 with enones 3. In these reactions the products
were also formed by participation of the endocyclic nitro-
gen atom. Thus, heating of the benzimidazoles 20a–d and
enone 3a in toluene or enone 3b or 3c in HMPA, gave py-
rido[1,2-a]benzimidazoles 23 in high yields. Under milder
reaction conditions (in acetonitrile at 10 °C) either com-
pounds 21 (with EWG = CN) or 22 (with EWG = CO2Me,
COPh, CONHCH2Ph) were formed. The products 23
were also obtained by heating compounds 21 or 22
(Scheme 5).
The products 26b and 27 gave satisfactory elemental anal-
1
yses and spectroscopic data (IR, H, 13C and 19F NMR),
which are consistent with the assigned structures. The
NMR spectra of the products 23a and 23c were identical
to those of the corresponding samples obtained from
enone 3a.
The nature of both the EWG and the polyfluoroalkyl
groups play a crucial role in product formation. Substitu-
tion of one fluorine with a chlorine atom in the trifluoro-
methyl group leads to increased stability of the products
21e and 22f, which gave the corresponding pyridobenz-
imidazoles 23e and 23f only under forcing conditions
(HMPA, 120 °C), compared to its trifluoromethyl ana-
logues 21a and 22b–d (toluene, 110 °C). Moreover, the
products 21h and 22i, bearing perfluoropropyl groups, are
the most stable. Compound 21h did not react even under
In contrast to enone 3a, compound 24 reacted easily with
benzthiazoles 28b–d at room temperature to form prod-
ucts 30b–d in high yields, whereas the chemical outcome
of the reaction with N-methylbenzimidazole 28a depend-
ed strongly on the temperature (Scheme 7).
While compound 30a was formed as the sole product at
45 °C, an approximate 1:1 mixture of products 29 and 30
Synthesis 2007, No. 24, 3797–3806 © Thieme Stuttgart · New York

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N. A. Tolmachova et al.
PAPER
COCF3
Me
N
H
N
CN
EWG
BuO
COCF3
EWG
N
24
N
H
N
MeCN, r.t.
EWG
X
N
N
H
F3COC
24
COCF3
F3C
COCF3
OH
26a–c
29
i
ii
+
20a,b; 25
EWG
X
N
100 °C, HMPA
28a–d
EWG
N
N
F3C
COCF3
OH
(i) HMPA, 25–30 °C:
(ii) HMPA, r.t. or 45 °C
30a–d
F3C
23a,c; 27
20a, 26a 20b, 26b 25, 26c, 27
28,29,30
a
b
c
d
EWG
CN
COOMe
SO2Ph
EWG CN CN COPh SO2Ph
X
NMe S
S
S
Scheme 6
Scheme 7
observed spectroscopically. If a thiazole ring is in the
starting methylene compounds, pyrones 9 or pyridones 14
were formed, owing to participation of the ester or nitrile
groups, respectively. In other cases, imidazo- (19), benz-
imidazo- (23, 27) or benzthiazo- (30) pyridines were ob-
tained by participation of the nitrogen atom of the
corresponding azole rings. High yields and simple prepa-
ration of the new polyfunctional compounds open a good
possibility to use them as polyfluoroalkylated building
blocks, particularly for the synthesis of biologically active
compounds.
Melting points are uncorrected. 1H, 13C and 19F NMR spectra were
recorded on Varian VXR (300 MHz), Varian Unian Plus (400 MHz)
and Bruker Avance DRX (500 MHz) instruments, using TMS and
CCl3F as internal standards. IR spectra were recorded on a Specord
M-80 spectrometer. Column chromatography was performed on sil-
ica gel 60 (Merck). Yields, physical constants and NMR data are
shown in Table 1 and Table 2.
Figure 2 Crystal structure of methyl 1-hydroxy-2-(trifluoroacetyl)-
1-(trifluoromethyl)-1,5-dihydropyrido[1,2-a]benzimidazole-4-car-
boxylate (26b).
The following compounds were prepared by literature methods: 4-
ethoxy-1,1,1-trifluorobut-3-en-2-one,19 1-chloro-4-ethoxy-1,1-di-
fluorobut-3-en-2-one,11b 1-ethoxy-4,4,5,5,6,6,6-heptafluorohex-1-
en-3-one,11b 3-ethoxymethylene-1,1,1,5,5,5-hexafluoropentane-2,4-
dione.20 All other reagents were obtained from usual commercial
sources or Enamine Ltd. (Kiev). All solvents and liquid reagents
were distilled before use.
was observed at room temperature (19F NMR), and com-
pound 29 was obtained as the main product at 10 °C. Ini-
tial formation of compound 29 was confirmed by its
cyclization to highly pure product 30a by stirring in
HMPA at 25–30 °C. The products 29 and 30a–d had
satisfactory elemental analyses and spectroscopic data
(IR, 1H, 13C and 19F NMR), which are consistent with the
assigned structures.
Synthesis of Compounds 7a–c; General Procedure
A mixture of ethyl (4-methyl-1,3-thiazol-2-yl)acetate (6; 300 mg,
1.6 mmol) and enone 3a–c (1.6 mmol) was heated in a tube with a
Teflon-lined screw-cap at 60 °C for 0.5 h. The reaction mixture was
stirred at r.t. overnight then the solid was treated with an Et2O–hex-
ane mixture (1:5), filtered, dried in air and crystallized (CCl4).
In summary, the chemical outcome of the reaction be-
tween fluorinated enones 3, 24 and various heterocycles
bearing a methylene group activated by an electron-with-
drawing substituent, depends on the nature of the hetero-
cyclic ring, the electron-withdrawing power of the
polyfluoroalkyl groups and the reaction conditions.
Synthesis of Pyrones 9a–c; General Procedure
A solution of compound 7 (1.0 mmol) in anhydrous AcOH (5 mL)
was heated at 100 °C for 30–50 h. The progress of the reaction was
monitored by TLC (hexane–EtOAc, 2:1; Rf ~0.5–0.6). The solvent
was evaporated and the residue was purified by column chromatog-
raphy (silica gel; hexane–EtOAc, 4:1; Rf ~0.4) and crystallized
(hexane).
In all cases, the reaction started with a nucleophilic attack
of the methylene carbon atom on the b-position of the
enones, followed by heterocyclization. In a number of
cases, the initial intermediate products were isolated or
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Polyfluoroalkyl-Containing Pyrones, Pyridones and Pyridobenzazoles
3801
Table 1 Physical Properties and Elemental Analysis Data for Synthesized Products
Compd Mp (°C) IR (CHCl3 or KBr) (cm–1)
Found (%)
Formula
Calcd (%)
C
H
N
C
H
N
7a
155–156 2984, 2336, 1675, 1640, 1552, 1488, 1400,
1376, 1240, 1192, 1141, 1072, 1040
46.92
3.88
4.01
2.92
2.25
2.20
2.00
2.90
2.71
4.67
C12H12F3NO3S
46.90
3.94
3.74
2.97
2.32
2.18
1.67
2.86
2.71
4.56
3.74
3.44
7b
7c
159–160 3670, 3124, 3058, 3025, 2983, 1717, 1692,
1637, 1495, 1232, 1068, 1041, 970
44.58
41.30
46.01
43.19
39.84
43.27
46.38
4.28
3.31
C12H12ClF2NO3S 44.52
174–175 3060, 2986, 1640, 1552, 1488, 1232, 1120,
1040, 900
C14H12F7NO3S
41.28
45.98
43.26
39.90
43.30
46.15
9a
144–145 3112, 3060, 1741, 1512, 1444, 1384, 1368,
1352, 1304, 1203, 1159, 1096
5.40 C10H6F3NO2S
4.98 C10H6ClF2NO2S
4.00 C12H6F7NO2S
7.18 C14H11F7N2OS
10.84 C10H7F3N2OS
5.36
9b
9c
131–132 3944, 3120, 1672, 1649, 1589, 1528, 1450,
1424, 1248, 1196, 979, 824
5.04
3.88
112–113 3944, 3696, 1744, 1441, 1351, 1232, 1192,
1128, 1064
13c
14a
126–127 3490, 3051, 1709, 1476, 1425, 1400, 1277,
1204, 1112, 930, 840
7.21
194–195 3058, 2988, 1656, 1592, 1528, 1505, 1452,
1428, 1393, 1346, 1304, 1248, 1217, 1187,
1145, 1108, 1012
10.76
14b
14c
14d
191–192 3060, 1712, 1529, 1449, 1424, 1390, 1361,
1320, 1248, 1224, 1144, 1096, 981
43.39
39.98
55.97
2.58
2.06
2.70
10.18 C10H7ClF2N2OS
7.84 C12H7F7N2OS
8.76 C15H9F3N2OS
43.41
40.01
55.90
2.55
1.96
2.81
10.12
7.78
8.69
192–193 3044, 1744, 1441, 1351, 1232, 1192, 1128,
900, 840
240–241 3408, 1653, 1557, 1502, 1479, 1444, 1400,
1360, 1302, 1358, 1208, 1184, 1136, 1112,
1096, 992, 912, 827
17
278–295 2200, 1765, 1643, 1612, 1584, 1576, 1452,
1375, 1296, 1244, 1176, 1138, 1121, 1040
49.63
53.18
56.00
3.47
2.76
2.91
17.05 C10H8F3N3O
18.34 C10H6F3N3
14.98 C13H8F3N3O
49.39
53.34
55.92
3.32
2.69
2.89
17.28
18.66
15.05
19
304–305 2210, 1656, 1642, 1587, 1576, 1480, 1386,
1310, 1177, 1141, 1110, 1072
21a
302–303 2324, 2208, 1776, 1634, 1620, 1587, 1544,
1472, 1425, 1385, 1296, 1244, 1224, 1176,
1138, 1111, 1070, 1004
21e
21h
22b
22f
22i
299–300 2334, 2205, 1696, 1648, 1632, 1588, 1539,
1472, 1387, 1281, 1254, 1212, 1136, 1104,
1071, 1008
52.89
47.46
63.72
60.91
54.98
59.28
2.64
2.05
3.57
3.44
2.88
3.01
14.14 C13H8ClF2N3O
11.00 C15H8F7N3O
7.88 C19H13F3N2O2
7.51 C19H13ClF2N2O2
6.05 C21H13F7N2O2
15.99 C13H6F3N3
52.81
47.51
63.69
60.89
55.03
59.76
2.73
2.13
3.66
3.50
2.86
2.32
14.21
11.08
7.82
314–315 2208, 1648, 1632, 1588, 1536, 1488, 1392,
1344, 1284, 1264, 1223, 1180, 1152, 1116,
1072, 1008
131–132 1632, 1572, 1501, 1480, 1427, 1381, 1342,
1320, 1269, 1272, 1256, 1200, 1160, 1134,
1064, 1040, 1016, 939, 827, 744, 691
129–130 1632, 1568, 1480, 1384, 1344, 1312, 1294,
1264, 1160, 1136, 1072, 1045, 1016, 992,
952, 848, 789, 744, 728, 704
7.47
159–160 1632, 1576, 1520, 1437, 1384, 1341, 1288,
1235, 1216, 1184, 1168, 1136, 1112, 1064,
1040, 1000, 852, 728, 704, 680
6.11
23a
239–240 2208, 1648, 1632, 1587, 1540, 1472, 1386,
1298, 1246, 1177, 1138, 1112, 1072
16.09
Synthesis 2007, No. 24, 3797–3806 © Thieme Stuttgart · New York

3802
N. A. Tolmachova et al.
PAPER
Table 1 Physical Properties and Elemental Analysis Data for Synthesized Products (continued)
Compd Mp (°C) IR (CHCl3 or KBr) (cm–1)
Found (%)
Formula
Calcd (%)
C
H
N
C
H
N
23b
23c
144–145 3685, 1712, 1676, 1584, 1480, 1456, 1417,
1400, 1362, 1296, 1224, 1168, 1144, 1120
67.03
3.30
8.23 C19H11F3N2O
67.06
3.26
8.23
111–112 3096, 1723, 1608, 1560, 1520, 1480, 1456,
1440, 1376, 1304, 1250, 1194, 1168, 1144,
1098, 1062
57.15
65.00
3.06
9.50 C14H9F3N2O2
57.15
65.04
3.08
9.52
23d
156–157 3060, 2988, 1712, 1627, 1632, 1568, 1552,
1520, 1480, 1456, 1420, 1316, 1260, 1207,
1168, 1147, 1096
3.84
11.41 C20H14F3N3O
3.82
11.38
23e
23f
192–193 3060, 2240, 1512, 1472, 1442, 1360, 1328,
1248, 1220, 1148, 1097, 984
55.80
64.00
2.87
3.09
15.03 C13H6ClF2N3
7.83 C19H11ClF2N2O
56.21
63.97
2.18
3.11
15.14
7.85
138–139 3051, 1673, 1600, 1518, 1480, 1449, 1424,
1381, 1284, 1208, 1171, 1144, 1120, 1088,
1088, 992
23i
164–165 3050, 1674, 1448, 1424, 1384, 1344, 1232,
1216, 1144, 1120, 944
57.25
47.03
2.50
2.50
6.40 C21H11F7N2O
6.82 C16H10F6N2O4
57.28
47.07
2.52
2.47
6.36
6.86
26b
228–229 1928, 1684, 1600, 1536, 1488, 1464, 1392,
1372, 1336, 1289, 1251, 1145, 1000, 960,
926, 762, 712, 696
27
186–185 3060, 1640, 1528, 1480, 1448, 1424, 1368,
1328, 1312, 1269, 1260, 1206, 1156, 1120,
1088, 952
57.10
3.44
7.38 C18H13F3N2O2S
57.14
3.46
7.40
29
241–242 1634, 1543, 1496, 1464, 1408, 1304, 1259,
1187, 1160, 1104, 808, 744, 688
49.42
49.43
45.91
2.28
2.35
1.58
10.64 C16H9F6N3O2
10.81 C16H9F6N3O2
7.17 C15H6F6N2O2S
49.39
49.39
45.93
2.31
2.31
1.54
10.76
10.76
7.14
30a
30b
167–168 3350, 2221, 1637, 1585, 1476, 1346, 1266,
1200, 1185, 1108, 1091
186–187 1624, 1582, 1487, 1356, 1312, 1256, 1192,
1138, 1104, 1050, 1024, 984, 920, 881, 800,
752
30c
30d
178–179 1601, 1552, 1480, 1370, 1302, 1216, 1184,
1152, 1107, 984, 865, 768, 744, 712, 688
53.48
47.29
2.38
2.23
3.01 C21H11F6NO3S
2.71 C20H11F6NO4S2
53.51
47.34
2.35
2.19
2.97
2.62
195–196 1621, 1561, 1476, 1376, 1346, 1263, 1232,
1185, 1144, 1088, 1018, 984, 928, 760, 688
Table 2 Selected Physical and Spectral Data of Synthesized Products
Yield 19F NMR [d (ppm)] 1H NMR [d (ppm)]
Compd
(solvent) (%)
13C NMR [d (ppm)]
7a
(CDCl3)
58
84
87
–77.84 (s)
1.37 (3 H, t, J = 6.7 Hz, CH3), 2.36 (3 H, s, CH3), 13.7, 14.3, 60.0, 98.0, 106.5, 116.2 (q, J =
4.30 (2 H, q, J = 6.7 Hz, CH2), 6.38 (1 H, d,
J10,11 = 15.1 Hz, H-10), 6.49 (1 H, s, H-2), 8.39
(1 H, d, J11,10 = 15.1 Hz, H-11), 13.12 (1 H, s, NH)
270.9 Hz), 118.7, 134.9, 144.5, 150.9, 164.3,
179.0 (q, J = 39.8 Hz)
7b
(CDCl3)
–67.34 (s)
1.38 (3 H, t, J = 6.7 Hz, CH3), 2.37 (3 H, s, CH3), 13.7, 14.3, 60.0, 98.0, 104.0, 114.2 (t, J =
4.31 (2 H, q, J = 6.7 Hz, CH2), 6.42 (1 H, d,
J10,11 = 15.7 Hz, H-10), 6.47 (1 H, s, H-2), 8.38
(1 H, d, J11,10 = 15.7 Hz, H-11), 13.11 (1 H, s, NH)
304.8 Hz), 119.0, 136.0, 144.5, 160.9, 167.9,
179.01 (t, J = 23.4 Hz)
7c
(CDCl3)
–80.43 (3 F, t, J = 9.2
Hz), –120.26 (2 F, q,
J = 9.2 Hz), –126.44
(2 F, s)
1.39 (3 H, t, J = 7.1 Hz, CH3), 2.38 (3 H, s, CH3), 13.7, 14.3, 60.9, 92.7, 104.6, 105.3, 137.5,
4.31 (2 H, q, J = 7.1 Hz, CH2), 6.40 (1 H, d,
J10,11 = 15.1 Hz, H-10), 6.49 (1 H, s, H-2), 8.39
(1 H, d, J11,10 = 15.1 Hz, H-11), 12.94 (1 H, s, NH)
144.4, 168.1, 168.8, 178.6 (t, J = 27.9 Hz)a
Synthesis 2007, No. 24, 3797–3806 © Thieme Stuttgart · New York

PAPER
Polyfluoroalkyl-Containing Pyrones, Pyridones and Pyridobenzazoles
3803
Table 2 Selected Physical and Spectral Data of Synthesized Products (continued)
Yield 19F NMR [d (ppm)] 1H NMR [d (ppm)]
Compd
(solvent) (%)
13C NMR [d (ppm)]
9a
(CDCl3)
46
25
43
–79.69 (s)
–61.52 (s)
2.44 (3 H, s, CH3), 6.80 (1 H, d, J10,11 = 7.2 Hz, 17.1, 105.5 (q, J = 3.4 Hz), 117.9 (q, J =
H-10), 7.08 (1 H, s, H-5), 8.42 (1 H, d, J11,10
=
270.9 Hz), 118.7, 123.8, 135.9, 147.6 (q, J =
7.2 Hz, H-11)
39.8 Hz), 156.5, 157.9
9b
(CDCl3)
2.43 (3 H, s, CH3), 6.75 (1 H, d, J10,11 = 6.4 Hz, 17.1, 105.5 (t, J = 3.4 Hz), 118.0 (t, J = 304.8
H-10), 7.07 (1 H, s, H-5), 8.43 (1 H, d, J11,10
=
Hz), 119.1, 123.8, 136.0, 147.6 (t, J = 23.4
6.4 Hz, H-11)
Hz), 154.9, 156.9
9c
(CDCl3)
–80.98 (3 F, t, J = 9.2
Hz), –118.29 (2 F, q,
J = 9.2 Hz), –126.95
(2 F, s)
2.52 (3 H, s, CH3), 6.91 (1 H, d, J10,11 = 6.3 Hz, 17.1, 107.9 (t, J = 5.1 Hz), 118.9, 123.7,
H-10), 7.16 (1 H, s, H-5), 8.50 (1 H, d, J11,10
6.3 Hz, H-11)
=
135.6, 147.6 (t, J = 30.4 Hz), 154.3, 156.4,
157.8a
13c
(CDCl3)
3
–80.79 (3 F, t, J = 8.5
Hz), –115.33 (2 F, q,
J = 8.5 Hz), –126.94
(2 F, s)
1.47 (3 H, t, J = 7.2 Hz, CH3), 2.46 (3 H, s, CH3), 13.3, 16.0, 62.6, 114.3 (t, J = 4.7 Hz), 115.6,
4.56 (2 H, q, J = 7.2 Hz, CH2), 6.99 (1 H, s, H-5), 118.7, 143.9 (t, J = 26.2 Hz), 152.1, 157.4,
7.31 (1 H, d, J11,10 = 7.6 Hz, H-11), 8.72 (1 H, d, 158.0a
J10,11 = 7.6 Hz, H-10)
14a
(CDCl3)
35
74
83
–68.32 (s)
2.55 (3 H, s, CH3), 7.04 (1 H, s, H-5), 7.20 (1 H, 16.8, 111.0, 115.2, 120.4 (q, J = 275.6 Hz),
d, J10,11 = 7.0 Hz, H-10), 8.22 (1 H, d, J11,10 = 7.0 136.1 (q, J = 40.3 Hz), 136.4, 152.6, 161.5,
Hz, H-11), 13.41 (1 H, s, NH)
163.2
14b
(CDCl3)
–57.32 (s)
2.54 (3 H, s, CH3), 7.03 (1 H, s, H-5), 7.7 (1 H, br 16.8, 108.4, 115.6, 120.5 (q, J = 275.6 Hz),
d, J10,11 = 7.2 Hz, H-10), 8.22 (1 H, br d,
J11,10 = 7.2 Hz, H-11), 13.30 (1 H, br s, NH)
13.10 (t, J = 30.1 Hz), 136.5, 152.6, 161.5,
164.0
14c
(CDCl3)
–80.63 (3 F, t, J = 8.8
Hz), –115.17 (2 F, q, J br d, J10,11 = 7.2 Hz, H-10), 8.30 (1 H, br d,
2.53 (3 H, s, CH3), 7.05 (1 H, s, H-5), 7.15 (1 H, 16.6, 112.6, 115.3, 136.1, 142.8 (m) 152.7,
161.2, 163.0a
= 8.8 Hz), –126.64
(2 F, s)
J11,10 = 7.2 Hz, H-11), 13.45 (1 H, br s, NH)
14d
(CDCl3)
58
–68.41 (s)
7.17 (1 H, br d, J10,11 = 7.2 Hz, H-10), 7.45 (3 H, 110.4, 114.2, 115.9, 118.5 (q, J = 245.7 Hz),
m, H-14, H-15, H-16), 7.65 (1 H, s, H-5), 7.93 118.5, 126.5, 128.9 (q, J = 31.0 Hz), 129.0,
(2 H, m, H-13, H-17), 8.46 (1 H, br d, J11,10 = 7.6 133.0, 136.7, 155.3, 161.2
Hz, H-11)
17
(CDCl3)
64
42
91
95
93
76
–74.58 (s)
–65.48 (s)
–75.97 (s)
–63.49 (s)
2.36 (3 H, s, CH3), 6.41 (1 H, d, J8,7 = 15.0 Hz, H- 16.0, 74.5, 106.2, 110.0 (br m), 115.8, 121.0
8), 6.47 (1 H, s, H-4), 8.39 (1 H, d, J7,8 = 15.0 Hz, (q, J = 292.2 Hz), 127.7, 137.2, 154.0, 174.1
H-7), 13.04 (2 H, br s, NH)
(q, J = 35.0 Hz)
19
(CDCl3)
2.38 (3 H, s, CH3), 6.97 (1 H, s, H-5), 7.82 (1 H, 13.2, 95.4, 106.7 (q, J = 4.7 Hz), 116.5 (q,
d, J8,7 = 7.3 Hz, H-8), 8.07 (1 H, d, J7,8 = 7.3 Hz, J = 275.8 Hz), 116.8, 123.2, 125.0 (q, J =
H-7)
37.8 Hz), 131.4, 134.0, 149.0
21a
(DMSO-
d6)
5.89 (1 H, d, J11,12 = 13.3 Hz, H-11), 7.33 (2 H, m, 67.8, 97.6, 111.8, 117.3, 117.89 (q, J = 292.2
H-6, H-9), 7.43 (2 H, m, H-7, H-8), 8.42 (1 H, d, Hz), 124.0, 131.5, 147.1, 150.3, 173.1 (q, J =
J12,11 = 13.3 Hz, H-13), 13.67 (2 H, br s, H-3, H-1) 31.3 Hz)
21e
(DMSO-
d6)
5.87 (1 H, d, J11,12 = 13.1 Hz, H-11), 7.29 (2 H, m, 68.0, 96.9, 112.3, 117.9, 122.5 (t, J = 304.6
H-7, H-8), 7.43 (2 H, m, H-6, H-9), 8.36 (1 H, d, Hz), 124.5, 132.4, 147.8, 150.7, 176.2 (t, J =
J12,11 = 13.1 Hz, H-12), 13.56 (1 H, br s, H-3, H-1) 23.4 Hz)
21h
(DMSO-
d6)
–80.69 (3 F, t, J = 8.2
Hz), –120.40 (2 F br
m), –126.64 (2 F, br s) J12,11 = 13.2 Hz, H-12), 13.64 (2 H, br s, H-3, H-1)
5.93 (1 H, d, J11,12 = 13.2 Hz, H-11), 7.44 (2 H, m, 68.9, 99.1, 112.3, 117.7, 124.5, 132.0, 147.3,
H-6 H-9), 7.29 (2 H, m, H-7, H-8), 8.40 (1 H, d,
150.7, 174.7 (t, J = 22.80 Hz)a
22b
(CDCl3)
–83.69 (s)
4.99 (1 H, d, J3,4 = 10.0 Hz, H-3), 6.80 (1 H, d,
J4,3 = 10.0 Hz, H-4), 7.24 (2 H, m, H-11, H-12),
78.2, 88.9 (q, J = 39.3 Hz), 90.6, 105.2,
113.6, 115.3, 122.9, 124.0, 128.1, 128.2,
7.49 (5 H, s, H-22, H-23, H-24, H-25, H-26), 7.72 129.7, 129.8, 129.9 (q, J = 272.5 Hz), 138.6,
(1 H, m, H-13), 7.83 (1 H, m, H-10), 8.86 (1 H, s, 149.5, 180.7
OH), 13.25 (1 H, s, NH)
Synthesis 2007, No. 24, 3797–3806 © Thieme Stuttgart · New York

3804
N. A. Tolmachova et al.
PAPER
Table 2 Selected Physical and Spectral Data of Synthesized Products (continued)
Compd
(solvent) (%)
Yield 19F NMR [d (ppm)]
1H NMR [d (ppm)]
13C NMR [d (ppm)]
22f
(CDCl3)
83
–65.53 (s)
5.23 (1 H, d, J3,4 = 10.4 Hz, H-3), 6.86 (1 H, d,
J4,3 = 10.4 Hz, H-4), 7.31 (2 H, m, H-11, H-12),
78.2, 88.9 (t, J = 26.1 Hz), 90.6, 105.2,
113.6, 115.3, 122.9, 124.0, 128.1, 128.2,
7.44 (3 H, m, H-22, H-24, H-26), 7.53 (2 H, m, H- 129.7, 129.8, 129.9 (t, J = 309.0 Hz),
25, H-23), 7.07 (1 H, m, H-13), 7.85 (1 H, m, H- 138.6, 149.5, 180.7
10), 8.00 (1 H, s, OH), 13.17 (1 H, br s, NH)
22i
(CDCl3)
43
–80.80 (3 F, t, J = 8.2
Hz), –119.00 (2 F, br
4.95 (1 H, d, J3,4 = 10.1 Hz, H-3), 6.78 (1 H, d,
J4,3 = 10.1 Hz, H-4), 7.29 (2 H, m, H-11, H-12),
88.0, 88.8, 90.6, 101.7, 113.2, 115.4, 123.3,
124.7, 128.2, 128.6, 129.7, 130.0, 130.4,
m), –123.96 (2 F, br s) 7.47 (5 H, s, H-22, H-23, H-24, H-25, H-26), 7.70 131.9, 140.5, 148.2, 174.8 (t, J = 27.9 Hz)a
(1 H, m, H-13), 7.84 (1 H, m, H-10), 9.06 (1 H, s,
OH), 13.21 (1 H, br s, NH)
23a
(CDCl3)
85
94
56
–65.24 (s)
–65.70 (s)
–65.86 (s)
7.57 (1 H, m, H-6), 7.69 (2 H, m, H-8, H-7), 8.04 106.4, 112.0, 114.6, 115.1, 120.3 (q, J =
(1 H, d, J11,12 = 7.8 Hz, H-11), 8.09 (1 H, d, 271.8 Hz), 121.0, 124.2, 127.4, 127.8, 129.7
J12,11 = 7.8 Hz, H-12), 8.33 (1 H, d, J9,8 = 7.3 Hz, (q, J = 36.2 Hz), 136.6, 144.6, 146.4
H-9)
23b
(CDCl3)
7.47 (4 H, m, H-Ar), 7.59 (3 H, m, H-Ar), 7.94
110.0 (q, J = 6.6 Hz), 114.2 (q, J = 6.6 Hz),
(2 H, m, H-6, H-11), 8.00 (1 H, d, J12,11 = 8.1 Hz, 120.5 (q, J = 273.2 Hz), 123.3, 126.4, 126.5,
H-12), 8.18 (1 H, d, J9,8 = 8.6 Hz, H-9)
127.4, 128.6 (q, J = 36.8 Hz), 128.6, 133.0,
134.2, 136.0, 145.0 146.1 192.4
23c
(CDCl3)
4.01 (3 H, s, CH3), 7.35 (1 H, d, J11,12 = 7.8 Hz, H- 53.0, 106.4, 111.9, 114.6, 115.1, 120.0 (q,
11), 7.51 (1 H, m, H-8), 7.62 (1 H, m, H-7), 7.95 J = 271.8 Hz), 124.3, 127.4, 127.8, 129.7 (q,
(1 H, d, J12,11 = 7.8 Hz, H-12), 8.44 (1 H, d,
J = 36.2 Hz), 137.0, 144.0, 146.5, 160.5
J6,7 = 7.3 Hz, H-6), 9.43 (1 H, d, J9,8 = 7.3 Hz, H-
9)
23d
(CDCl3)
76
–65.32 (s)
4.86 (2 H, d, J = 6.1 Hz, CH2), 7.34 (3 H, m, H-
Ar), 7.49 (4 H, m, H-Ar), 7.62 (1 H, m, H-8), 7.96 Hz), 120.3, 120.5 (q, J = 272.9 Hz), 124.8,
43.9, 111.3 (q, J = 7.8 Hz), 114.5 (q, J = 7.8
(1 H, d, J12,11 = 7.4 Hz, H-12), 8.16 (1 H, br d,
J6,7 = 8.8 Hz, H-6), 8.57 (1 H, d, J11,12 = 7.4 Hz,
H-11), 11.13 (1 H, br s, NH)
126.8, 127.4, 127.5, 128.7 (q, J = 35.3 Hz),
129.1, 130.4, 138.3, 143.5, 146.6, 162.1
23e
(CDCl3)
79
83
73
95
–51.64 (s)
–53.56 (s)
7.16 (1 H, m, H-9), 7.53 (1 H, m, H-8), 7.65 (1 H, 99.4 (t, J = 3.5 Hz), 105.3 (t, J = 5.4 Hz),
m, H-7), 7.99 (1 H, d, J12,11 = 7.7 Hz, H-12), 8.07 111.1, 111.7, 121.2, 123.1 (t, J = 28.3 Hz),
(1 H, d, J11,12 = 7.7 Hz, H-11), 8.78 (1 H, d,
J6,7 = 6.1 Hz, H-6)
123.9, 127.9, 128.5, 129.5, 141.4 (t, J = 28.3
Hz), 144.5, 145.3
23f
(CDCl3)
7.47 (4 H, m, H-Ar), 7.59 (3 H, m, H-Ar), 7.65
109.2 (t, J = 8.0 Hz), 115.9 (t, J = 7.6 Hz),
(1 H, m, H-Ar), 7.94 (2 H, m, H-Ar), 8.00 (1 H, d, 121.5 (t, J = 288.2 Hz), 123.1, 126.3, 126.6,
J12,11 = 7.8 Hz, H-12), 8.18 (1 H, d, J11,12 = 7.8 Hz, 127.5, 128.6, 130.4, 132.5, 133.9 (t, J = 33.7
H-11)
Hz), 134.2, 136.0, 145.1, 146.3, 192.4
23i
(CDCl3)
–80.13 (3 F, t, J = 8.8
Hz), –107.44 (2 F, q,
J = 8.8 Hz), –123.33
(2 F, s)
7.44 (4 H, m, H-Ar), 7.59 (3 H, m, H-Ar), 7.94
113.7 (t, J = 9.7 Hz), 115.1 (t, J = 11.5 Hz),
(2 H, m, H-6, H-11), 8.00 (1 H, d, J12,11 = 8.1 Hz, 121.2, 123.2, 125.8, 126.3, 128.1 (t, J = 32.2
H-12), 8.09 (1 H, d, J9,8 = 8.6 Hz, H-9)
Hz), 128.2, 128.7, 133.6, 132.5, 134.2, 135.9,
145.0, 146.5, 192.3a
26b
(DMSO-
–66.88 (3 F, s),
–80.58 (3 F, s)
3.57 (3 H, s, CH3), 7.15 (2 H, m, H-11, H-12),
52.0, 89.0, 89.3 (q, J = 35.0 Hz), 97.4, 116.8
7.45 (1 H, d, J10,11 = 7.8 Hz, H-10), 7.73 (1 H, d, (q, J = 2.3 Hz), 118.3 (q, J = 290.1 Hz), 125.6
d6)
J13,12 = 7.5 Hz, H-13), 9.04 (1 H, s, H-4), 9.05
(1 H, s, NH), 12.94 (1 H, s, OH)
(q, J = 296.7 Hz), 125.7, 126.5, 130.4, 131.7,
144.6 (q, J = 2.4 Hz), 146.7, 164.9, 176.4 (q,
J = 33.2 Hz)
27
(DMSO-
d6)
84
56
–66.02 (s)
–70.91 (s)
7.52 (6 H, m, H-7, H-8, H-12, H-23, H-24, H-25), 109.4 (q, J = 6.1 Hz), 114.0 (q, J = 6.1 Hz),
8.09 (2 H, m, H-6, H-11), 8.39 (3 H, m, H-9, H-
22, H-26)
119.9 (q, J = 272.6 Hz), 121.4, 123.6, 126.6,
127.2, 128.6, 129.1, 129.5, 131.0 (q, J = 36.1
Hz), 133.2, 133.9, 138.7, 144.7
29
(DMSO-
d6)
3.71 (3 H, s, CH3), 5.70 (1 H, d, J9,8 = 13.0 Hz, H- 32.1, 67.5, 98.3, 111.0, 112,1, 118.0, 118.5
9), 7.13 (2 H, m, H-12, H-8), 7.23 (1 H, m, H-7), (q, J = 296.3 Hz), 124.3, 125.1, 130.8, 133.6,
7.42 (1 H, s, NH), 8.08 (1 H, d, J6,7 = 13.6 Hz, H- 149.5, 149.9, 174.1 (q, J = 32.4 Hz)
6)
Synthesis 2007, No. 24, 3797–3806 © Thieme Stuttgart · New York

PAPER
Polyfluoroalkyl-Containing Pyrones, Pyridones and Pyridobenzazoles
3805
Table 2 Selected Physical and Spectral Data of Synthesized Products (continued)
Compd
(solvent) (%)
Yield 19F NMR [d (ppm)]
1H NMR [d (ppm)]
13C NMR [d (ppm)]
36.3, 79.6, 85.6 (q, J = 34.9 Hz), 104.0, 120.0
30a
(DMSO-
d6)
84
87
85
–67.13 (3 F, s),
–80.18 (3 F, s)
3.83 (3 H, s, CH3), 7.23 (2 H, m, H-12, H-11),
7.50 (1 H, s, H-4), 7.55 (1 H, d, J10,11 = 8.1 Hz, H- (q, J = 292.1 Hz), 120.7, 124.0, 126.3 (q, J =
10), 7.77 (1 H, d, J13,12 = 8.1 Hz, H-13), 9.23 (1 H, 296.7 Hz), 127.0, 127.9, 129.6, 142.0, 143.9,
s, OH)
169.3, 178.1 (q, J = 38.0 Hz)
30b
(DMSO-
d6)
–69.27 (3 F, s),
–85.22 (3 F, s)
7.48 (1 H, m, H-12), 7.57 (1 H, m, H-11), 7.92
(1 H, s, H-7), 8.03 (1 H, d, J10,11 = 8.7 Hz, H-10), J = 291.0 Hz), 120.9, 124.6, 125.6 (q, J =
8.39 (1 H, d, J13,12 = 8.7 Hz, H-13), 9.07 (1 H, s,
OH)
78.6, 89.3 (q, J = 35.0 Hz), 103.4, 119.0 (q,
296.8 Hz), 126.9, 127.9, 129.7, 141.5, 144.4
(q, J = 2.3 Hz), 165.3, 176.4 (q, J = 34.0 Hz)
30c
–69.20 (3 F, s),
–84.78 (3 F, s)
7.56 (7 H, m, H-12, H-11, H-30, H-29, H-28, H- 91.5 (q, J = 34.4 Hz), 103.5, 106.0, 119.1 (q,
31, H-27), 7.84 (1 H, d, J13,12 = 8.2 Hz, H-13), J = 287.9 Hz), 120.4, 121.0 (q, J = 297.3 Hz),
8.16 (1 H, s, H-7), 8.61 (1 H, d, J10,11 = 8.8 Hz, H- 121.3, 122.6, 128.5, 129.0, 129.2, 129.4,
(DMSO-
d6)
10), 9.30 (1 H, s, OH)
130.6, 137.2, 138.7, 145.4, 182.4 (q, J = 29.3
Hz), 190.0
30d
(DMSO-
91
–68.21 (3 F, s),
–87.04 (3 F, s)
7.51 (5 H, m, H-12, H-11, H-30, H-29, H-28),
7.71 (1 H, d, J13,12 = 7.9 Hz, H-13), 7.91 (2 H, m, J = 287.9 Hz), 120.4, 120.9 (q, J = 295.0 Hz),
82.9 (q, J = 34.4 Hz), 100.6, 106.0, 117.1 (q,
d6)
H-31, H-27), 8.22 (1 H, s, H-7), 8.51 (1 H, d,
J10,11 = 8.7 Hz, H-10), 9.26 (1 H, s, OH)
122.6, 128.5, 129.0, 129.2, 129.4, 132.9,
134.6, 138.8, 146.4, 162.5, 180.4 (q, J = 29.3
Hz)
a Signals arising from the carbon atoms of the C3F7 group are overlapping multiplets.
Synthesis of Pyridones 14a–d; General Procedure
under vacuum without extra heating and the residue was crystal-
lized (CCl4–CHCl3, 10:3).
A mixture of 1,3-thiazol-2-ylacetonitrile 10a,10b (1.0 mmol) and
enone 3a–c (1.0 mmol) in anhydrous AcOH (10 mL) was stirred at
r.t. for 10–15 h. The progress of the reaction was monitored by 19
F
Synthesis of 23a–d; General Procedure (Method 1)
A mixture of 2-substituted benzimidazole 20 (1.0 mmol) and b-
alkoxyvinyl polyfluoroalkyl ketone 3a (168 mg, 1.0 mmol) was re-
fluxed in anhydrous toluene (10 mL) for 6–12 h. The solvent was
carefully evaporated and the residue was crystallized (CCl4–hex-
ane).
NMR spectroscopy. The solvent was evaporated and the residue
was crystallized (CCl4).
(2E,3E)-6,6,6-Trifluoro-2-(4-methyl-1,3-dihydro-2H-imidazol-
2-ylidene)-5-oxohex-3-enenitrile (17)
A mixture of imidazole 16 (1.0 mmol) and enone 3a (168 mg, 1.0
mmol) in HMPA (5 mL) was stirred at r.t. for 10 h. The progress of
the reaction was monitored by 19F NMR spectroscopy. The reaction
mixture was quenched with H2O (15 mL) and the precipitated solid
was collected by filtration, dried under vacuum, and crystallized
(CHCl3–hexane, 1:10).
Synthesis of 23e–i; General Procedure (Method 2)
A mixture of 2-substituted benzimidazole 20 (1.0 mmol) and b-
alkoxyvinyl polyfluoroalkyl ketone 3a–c or product 21a, 21e, 22b,
22f, 22i (1.0 mmol) was stirred in anhydrous MeCN (5 mL) at 40 °C
for 12–24 h. The progress of the reaction was monitored by TLC
(EtOAc–hexane, 1:2; Rf ~0.3–0.4). The reaction mixture was
quenched with H2O (15 mL) and the precipitated solid was collected
by filtration, dried under vacuum and crystallized (CHCl3–hexane).
Preparation of 3-Methyl-5-(trifluoromethyl)imidazo[1,2-a]pyri-
dine-8-carbonitrile (19)
A mixture of imidazole 16 (1.0 mmol) and enone 3a (168 mg, 1.0
mmol) in HMPA (5 mL) was heated at 100 °C for 7 h. The progress
of the reaction was monitored by 19F NMR spectroscopy. The reac-
tion mixture was quenched with H2O (15 mL) and the precipitated
solid was collected by filtration, dried under vacuum, and crystal-
lized (CCl4).
Methyl 1-Hydroxy-2-(trifluoroacetyl)-1-(trifluoromethyl)-1,5-
dihydropyrido[1,2-a]benzimidazole-4-carboxylate (26b)
Methyl 1H-benzimidazol-2-ylacetate (20b; 190 mg, 1.0 mmol) and
1,1,1,5,5,5-hexafluoro-3-(isobutoxymethylene)pentane-2,4-dione
(24; 292 mg 1.0 mmol) was stirred in anhydrous MeCN (5 mL) at
r.t. for 6–12 h. The progress of the reaction was monitored by TLC
(EtOAc–hexane, 1:2; Rf = 0.3). The reaction mixture was quenched
with H2O (15 mL) and the precipitated solid was collected by filtra-
tion, dried under vacuum and crystallized (CHCl3).
Synthesis of 21a, 21e and 21h; General Procedure
The b-alkoxyvinyl polyfluoroalkyl ketone 3a–c (1.0 mmol) was
added to a solution of 1H-benzimidazol-2-ylacetonitrile (20a; 157
mg, 1.0 mmol) in anhydrous MeCN (5 mL) and the mixture was
stirred at r.t. for 1–2 h. The solvent was carefully evaporated with-
out extra heating and the residue was crystallized (MeCN–CHCl3,
5:1).
4-(Phenylsulfonyl)-1-(trifluoromethyl)pyrido[1,2-a]benz-
imidazole (27)
2-[(Phenylsulfonyl)methyl]-1H-benzimidazole (25; 272 mg, 1.0
mmol) and 1,1,1,5,5,5-hexafluoro-3-(isobutoxymethylene)pentane-
2,4-dione (24; 292 mg, 1.0 mmol) was stirred in anhydrous MeCN
(5 mL) at r.t. for 10 h. The progress of the reaction was monitored
by TLC (EtOAc–hexane, 1:2; Rf = 0.4). The reaction mixture was
quenched with H2O (45 mL) and the precipitated solid was collected
by filtration, dried under vacuum and crystallized (toluene).
Synthesis of 22b, 22h and 22; General Procedure
The b-alkoxyvinyl polyfluoroalkyl ketone 3a–c (1.0 mmol) was
added to a solution of 2-(1H-benzimidazol-2-yl)-1-phenylethanone
(20c; 236 mg, 1.0 mmol) in anhydrous MeCN (5 mL). The mixture
was stirred at r.t. for 6–8 h. The solvent was carefully evaporated
Synthesis 2007, No. 24, 3797–3806 © Thieme Stuttgart · New York

3806
N. A. Tolmachova et al.
PAPER
(2Z)-6,6,6-Trifluoro-2-(1-methyl-1,3-dihydro-2H-benzimid-
azol-2-ylidene)-5-oxo-4-(trifluoroacetyl)hex-3-enenitrile (29a)
A mixture of (1-methyl-1H-benzimidazol-2-yl)acetonitrile (28a;
171 mg, 1.0 mmol) and 1,1,1,5,5,5-hexafluoro-3-(isobutoxymethyl-
ene)pentane-2,4-dione (24; 292 mg, 1.0 mmol) was stirred in anhy-
drous HMPA (6 mL) at 10 °C for 3 h. The progress of the reaction
was monitored by TLC (EtOAc–hexane, 1:2; Rf = 0.3). The reaction
mixture was quenched with H2O (25 mL) and the precipitated solid
was collected by filtration, dried under vacuum and crystallized
(CCl4–hexane, 1:2).
References
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Hirohashi, T.; Kanno, T.; Iwaasa, H.; Kanatani, A.; Fukami,
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(4) Kelly, T.; Bell, S.; Osashi, N.; Armstrong-Chong, J. J. Am.
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1-Hydroxy-5-methyl-2-(trifluoroacetyl)-1-(trifluoromethyl)-
1,5-dihydropyrido[1,2-a]benzimidazole-4-carbonitrile (30a)
A mixture of (1-methyl-1H-benzimidazol-2-yl)acetonitrile (28a;
171mg 1.0 mmol) and 1,1,1,5,5,5-hexafluoro-3-(isobutoxymethyl-
ene)pentane-2,4-dione (24; 292 mg, 1.0 mmol) was stirred in anhy-
drous MeCN (10 mL) at 45 °C for 6 h. The progress of the reaction
was monitored by TLC (EtOAc–hexane, 1:2, Rf = 0.4). The reaction
mixture was quenched with H2O (25 mL) and the precipitated solid
was collected by filtration, dried under vacuum and crystallized
(CHCl3).
(5) (a) Cox, R.; O’Hagan, D. J. Chem. Soc., Perkin Trans. 1
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(12) Gerus, I. I.; Vdovenko, S. I.; Gorbunova, M. G.; Kukhar, V.
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Synthesis of 30b–d; General Procedure
A mixture of benzthiazole 28 (1.0 mmol) and 1,1,1,5,5,5-hexafluo-
ro-3-(isobutoxymethylene)pentane-2,4-dione (24; 292 mg, 1.0
mmol) was stirred in anhydrous MeCN (15 mL) at r.t. for 2–6 h. The
progress of the reaction was monitored by TLC (EtOAc–hexane,
1:2; Rf = 0.3). The reaction mixture was quenched with H2O (45
mL) and the precipitated solid was collected by filtration, dried un-
der vacuum, and crystallized (CHCl3).
Crystallographic data (excluding structure factors) for the reported
structure have been deposited with the Cambridge Crystallographic
Data Center as supplementary publication no. CCDC-651853. Cop-
ies of the data can be obtained free of charge on application to The
Director CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44(1223)336033, email:deposit@ccdc.cam.ac.uk].
(15) Gerus, I. I.; Tolmachova, N. A.; Vdovenko, S. I.; Fröhlich,
Acknowledgment
R.; Haufe, G. Synthesis 2005, 1269.
(16) Tolmachova, N. A.; Gerus, I. I.; Vdovenko, S. I.; Essers, M.;
Fröhlich, R.; Haufe, G. Eur. J. Org. Chem. 2006, 4704.
(17) Volovenko, Y. M.; Nemasanyii, A. G.; Ryabokon, I. G.;
Babichev, F. S. Ukr. Khim. Zh. 1988, 54, 295.
(18) Shaozhong, W.; Tan, T.; Jianxin, L.; Hongwen, H. Synlett
2005, 2658.
We are grateful to Enamine Ltd. (Kiev) for recording the NMR
spectra and for the supply of materials. The X-ray diffraction analy-
sis by Mrs S.V. Shishkina and Dr O.V. Shishkin (STC ‘Institute for
Single Crystals’, Kharkov) is gratefully acknowledged.
(19) Pazenok, S. V.; Gerus, I. I.; Chaika, E. A.; Yagupolskii, L.
M. J. Org. Chem. USSR (Engl. Transl.) 1989, 25, 1238.
(20) Hojo, R.; Masuda, M.; Okana, E. Synthesis 1990, 347.
Synthesis 2007, No. 24, 3797–3806 © Thieme Stuttgart · New York