Reaction of α-halogen substituted β-ethoxyvinyl trifluoromethyl ketones with 2-aminopyridine: New route to trifluoroacetyl-containing heterocycles

Article abstract of DOI:10.1016/S0022-1139(02)00190-2

The reaction of α-halosubstituted β-ethoxyvinyl trifluomethyl ketones with 2-aminopyridine gives 3-trifluoroacetyl imidazo [1,2-a]pyridine and 3-halo-1,1,1,-trifluoro-4-(2-pyridinylamino)-3-buten-2-ones. The product ratio depends on the nature of the α-halogen atom and the solvent.

Full text of DOI:10.1016/S0022-1139(02)00190-2

Journal of Fluorine Chemistry 117 (2002) 193±197
Reaction of a-halogen substituted b-ethoxyvinyl tri¯uoromethyl
ketones with 2-aminopyridine: new route to
tri¯uoroacetyl-containing heterocycles
Liliya M. Kacharova, Igor I. Gerus*, Alexey D. Kacharov
Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Sciences,
Murmanskaya 1, Kiev 02094, Ukraine
Received 19 April 2002; received in revised form 3 May 2002; accepted 26 June 2002
Dedicated to Professor Lev M. Yagupolskii on the occasion of his 80th birthday.
Abstract
The reaction of a-halosubstituted b-ethoxyvinyl tri¯uoromethyl ketones with 2-aminopyridine gives 3-tri¯uoroacetyl imidazo[1,2-
a]pyridine and 3-halo-1,1,1-tri¯uoro-4-(2-pyridinylamino)-3-buten-2-ones. The product ratio depends on the nature of the a-halogen atom
and the solvent.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Fluorinated a-enamino ketones; Enones; Amination; Cyclization; Bicyclic heterocyclic compounds
1. Introduction
with participation of halogen atoms that are obviously
impossible for enone 1.
Over the last several decades, the use of ¯uorine sub-
stitution to tailor the physical and chemical properties of
diverse organic compounds has been amply demonstrated
[1,2]. Thus, methods for the synthesis of tri¯uoromethylated
compounds have received considerable attention, especially
following the synthon approach [3,4]. Easily accessible b-
ethoxyvinyl tri¯uoromethyl ketone (1) [5,6], a chemical
equivalent of tri¯uoroacetyl acetaldehyde, can be considered
as a promising tri¯uoromethyl-containing C4-synthon for
the synthesis of various compounds, many of which have a
certain biological interest. Enone 1 has already been used for
the synthesis of dyes [7], heterocycles [8±15], drugs [5] and
as a protective reagent for amino groups in peptide synthesis
[16]. Recently, we have modi®ed this useful synthon by
adding one more reaction center to obtain a series of a-
halogenated enones 2a±c that generally have reactivity
similar to that of the starting enone 1 [17,18]. The presence
of halogen atom at the a-position, however, allows some
new reactions of a-haloenones 2a±c, such as cyclization
The reaction of 1,2- or 1,3-binucleophiles with enone 1 is
accompanied by heterocyclization with C=O group partici-
pation, and tri¯uoromethyl-containing heterocycles are
formed [8±15]. In case of the reaction of a-haloenones
2a±c with 1,3-binucleophiles, there is the possibility of
forming tri¯uoroacetyl-containing ®ve-member hetero-
cycles via participation of the halogen atoms at the a-
position. In this paper, we describe the results of our
investigation on the reaction of a-haloenones 2a±c with
2-aminopyridine as the 1,3-binucleophile.
2. Results and discussion
One of the most facile reactions of poly¯uoroacylated
vinyl ethers 1 and its a-halogenated derivatives 2a±c is the
replacement of the alkoxy group by amine moieties
[5,15,17,18]. This reaction gives the corresponding enamino
* Corresponding author. Tel.: ‡380-44-573-2598;
fax: ‡380-44-573-2552.
E-mail address: igerus@alfacom.net (I.I. Gerus).
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 1 9 0 - 2

194
L.M. Kacharova et al. / Journal of Fluorine Chemistry 117 (2002) 193±197
Scheme 1.
ketones in almost quantitative yields for enone 1 and with
40±80% yield for 2a±c. The reaction of 2-aminopyridine
with a-bromoenone 2b in chloroform, however, produced
not only enaminone 3b but also 3-tri¯uoroacetyl imi-
dazo[1,2-a]pyridine 4 as a main product (ratio 1/3) in high
total yield (Scheme 1).
This is the ®rst example of a cyclization reaction of a-
halogenated enones 2a±c with substitution of halogen
atoms. Since imidazopyridine 4 was previously unknown,
the position of the tri¯uoroacetyl group was determined on
the basis of the literature 1H and 19F NMR spectral data for
the known 3-chlorodi¯uoroacetyl imidazo[1,2-a]pyridine 8
[19]. We synthesized a sample of the compound 8 from a-
bromo-(b-ethoxyvinyl) chlorodi¯uoromethyl ketone 6 and
2-aminopyridine in DMF (conditions where enaminone 7 is
a minor product, see below). The starting a-bromoenone 6
was synthesized by the bromination of enone 5 as described
earlier [17] (Scheme 2).
These results attracted our attention because of the high
interest to biological properties of 3-acyl imidazo[1,2-a]pyr-
idines [20±23]. Despite numerous applications of the most
common route to this heterocyclic system Ð condensation
of 2-aminopyridines with a-halodicarbonyl compounds
[24]Ðalternative methods are still required [25±28] due
to possible low selectivity of the general approach.
Only few examples of the synthesis of related non-¯uori-
nated compounds, such as imidazoles, based on a-halo-b-
alkoxyvinyl carbonyl compounds are described in literature.
The reaction of a-halo-b-methoxyvinyl methyl ketone with
acetamidine [29] leads to 2-methyl-5-acetylimidazole
(together with 2,4-dimethyl-5-halosubstituted pyrimidines)
and the reaction of 2-bromo-3-(iso-propoxy)-2-propenal
with different non-cyclic amidines [30] yields mixtures of
isomeric 1,4- and 1,5-disubstituted imidazoles containing
aldehyde group at position 4 or 5. No enaminones and no
pyrimidines were found among the reaction products
[29,30].
On varying of the reaction conditions and structure of
starting enones 2a±c (Table 1) we have found that the change
of the halogen atom from Cl to I and increase of solvent
polarity generally result in preferred formation of imidazo-
pyridine 4. But surprisingly, the reaction in water produces
enaminones 3a and b as the only products, which will be
discussed below. Temperature has a negligible effect on
product ratio (for 2b in CHCl3 at À20 to 60 8C). Thus, by
varying the reaction conditions we can obtain enaminones
3a±c or 3-tri¯uoroacetyl imidazo[1,2-a]pyridine 4 as the
main product.
We propose possible reaction pathways to 4 in Scheme 3.
2-Aminopyridine contains two nucleophilic nitrogen sites
for attack on 2a±c. We found, however, that a-bromoenone
2b does not react with highly nucleophilic 4-dimethylami-
nopiridine (DMAP), which therefore excludes primary
attack of the pyridine ring nitrogen atom of 2-aminopyridine
on the a-carbon atom of enones 2a±c bearing not only the
halogen atom but also partial negative charge as a result of
strong polarization of carbon±carbon double bond. Thus, the
initial step of this reaction is attack of the NH2-group on the
b-carbon atom of a-haloenones 2a±c that usually gives
enaminones 3 after ethanol elimination. We have examined
the possibility of the formation of imidazopyridine 4 from
enaminones 3 via intramolecular nucleophilic attack of the
pyridine ring nitrogen atom on the a-carbon atom of enam-
inones 3. But treating enaminone 3b with bases, such as
Table 1
Ratiosa of products 3a±c/4 in the reactionb of enones 2a±c with 2-
aminopyridine in various solvents
Enone
Solvents
CHCl3
McCN
DMF
DMSO
H2O
2a
2b
2c
>99/<1
25/75
14/86
80/20
12/88
5/95
61/39
8/92
4/96
50/50
7/93
2/98
>99/<1
>99/<1
75/25
a Ratios of products were determined by 19F NMR analyses of crude
reaction mixtures.
b All reactions were run at 18±23 8C in the solvent indicated in the
table, reaction time was 24 h, ratio 2a±c/2-NH2Py ˆ 1/2, 0.5±5 mmol
scale.
Scheme 2.

L.M. Kacharova et al. / Journal of Fluorine Chemistry 117 (2002) 193±197
195
Scheme 3.
NEt3, DMAP, DBU, t-BuOKproduced no traces of imida-
zopyridine 4. This demonstrates that compound 4 is not
formed via intramolecular cyclization of enaminones 3a±c
under the basic conditions (Scheme 4).
nitrogen atom to the a-position to the carbonyl group
with the formation of intermediate B1. Subsequent intra-
molecular alkylation of the pyridine ring on nitrogen atom
leads to ring closure (intermediate B2). The a-halogen
atom mobility (Cl < Br < I) on saturated carbon atom
(intermediate B1) is consistent with the percentage of
imidazopyridine 4 in the reaction mixture (see Table 1).
The HX and EtOH eliminations then lead to the ®nal
imidazo[1,2-a]pyridine structure. Thus, the formation of
imidazopyridine 4 is possible only when the a-carbon atom
is protonated, which leads to the formation of an inter-
mediate type B1.
The suggested mechanism is also supported by the highly
selective and effective transformation of enaminone 3b and
c into imidazopyridine 4 upon heating (80 8C, 5 h) with 2 eq.
of 2-aminopyridine in DMF (monitored by 19F NMR). This
transformation proceeds through the intermediate B10
(Scheme 3) whose structure resembles that of intermediate
B1. Known re-amination reactions [31] of non-a-haloge-
nated analogs of enaminones 3a±c also suggests the addi-
tion±elimination mechanism. However, the rate of the re-
amination at room temperature is slow and this process does
not affect the product ratio in the reactions of a-haloenones
2a±c with 2-aminopyridine.
With the above explanation for the formation of imida-
zopyridine 4, we now consider the interaction of a-haloe-
nones 2a±c with 2-aminopyridine in detail. It is known that
enone 1 rapidly reacts with amines through the zwitterions,
followed by elimination of ethanol [15,31±33]. Because a-
haloenones 2a±c react with primary and secondary amines
in the same way forming corresponding a-haloenaminones
[17,18], we assume that the instant reaction proceeds
through a similar zwitterion Z (Scheme 3). Its further
transformations may lead to enaminones 3a±c or imida-
zopyridine 4 depending upon the reaction conditions. In
low polar solvents or in water (Scheme 3, route A) enam-
inones 3a±c are formed predominantly as a result of either
ethoxy anion and proton eliminations (not shown in
Scheme 3) or by proton migration to the oxygen atom of
the ethoxy group with the formation of intermediate A1.
The latter prevents the nucleophilic substitution of a-
halogen atom and facilitates ethanol elimination to produce
enaminones 3a±c. In polar solvents (route B), solvation of
the zwitterion Z favors the proton migration from the
In summary, we have found that a-halogenated enones
2a±c react with 2-aminopyridine to form enaminones 3a±c
or 3-tri¯uoroacetyl imidazo[1,2-a]pyridine 4. These ¯uori-
nated substances can be used as practical building blocks for
the synthesis of bioactive ¯uorinated compounds.
A broader investigation of the route to the synthesis of
various poly¯uoroacyl-containing heterocycles is now
underway.
Scheme 4.

196
L.M. Kacharova et al. / Journal of Fluorine Chemistry 117 (2002) 193±197
3. Experimental
3.1. General
J ˆ 8:9 Hz), 7.71 (m, 1H), 7.29 (m, 1H). 19F NMR: dF
À72.80 (s). Anal. Calcd. for C9H5F3N2O: C, 50.48; H,
2.35; N, 13.08. Found: C, 50.57; H, 2.50; N, 13.05.
1H and 19F NMR spectra were recorded on Varian VXR
instrument (300 and 282.2 MHz) in CDCl3 solutions using
TMS and CCl3F as internal standards, respectively. Solvents
were distilled and 2-aminopyridine was crystallized from
hexane before using. Starting enones were prepared accord-
ing to literature procedures 2a and b [17], 2c [18] and 5
[34,35].
3.4. (Z)-3-Bromo-4-ethoxy-1-chloro-1,1-difluorobut-3-
en-2-one (6)
Bromine (2.86 g, 17.9 mmol) was added dropwise to a
stirred solution of 3 g (16.3 mmol) of enone 1 in CHCl3
(15 ml) at 0±5 8C. After 20 min, pyridine (1.41 g, 17.9 mmol)
was added dropwise at the same temperature. After 30 min to
the reaction mixturewas added water (20 ml), thewater phase
was extracted with hexane (3 Â 10 ml). The combined
organic layers were dried by MgSO4 and the solvent was
evaporated. The residue was distilled in vacuum. Yield 3.62 g
(85%), bp 120±122 8C/16 mmHg. 1H NMR: dH 8.08 (s, 1H),
4.40 (q, 2H, J ˆ 7:0 Hz), 1.49 (t, 3H, J ˆ 7:0 Hz). 19F NMR:
dF À58.34 (s).
3.2. (E)-3-Bromo-1,1,1-trifluoro-4-(2-pyridinylamino)-3-
buten-2-ones (3b): typical procedure for enaminones 3a±c
To a stirred emulsion of haloenone 2b (0.4 g, 1.6 mmol) in
20 ml H2O was added solution of 2-aminopyridine (0.15 g,
1.6 mmol) in 5 ml H2O. After 2 h, the precipitated product
was ®ltered off, washed with water, dried and crystallized
from hexane. The yield of enaminone 3b is 0.33 g (70%) as
3.5. 3-Chlorodiuoroacetylimidazo[1,2-a]pyridine (8)
1
white needles (mp 128±129 8C). H NMR: dH 9.13 (d, 1H,
J ˆ 12:7 Hz), 8.38 (dm, 1H, J ˆ 4:7 Hz), 7.83 (br d, 1H,
J ˆ 8:2 Hz), 7.72 (m, 1H), 7.11 (m, 1H), 6.95 (d, 1H,
J ˆ 8:2 Hz). 19F NMR: dF À68.60 (s). Anal. Calcd. for
C9H6BrF3N2O: C, 36.64; H, 2.05; N, 9.49. Found: C, 36.72;
H, 2.01; N, 9.56.
The compound was synthesized in 72% yield as described
above for ketone 4 using 2-aminopyridine (1 g, 10.6 mmol)
and enone 6 (1.22 g, 4.6 mmol) in DMF (5 ml). Compound
8: white needles, mp 144±145 8C, [19] 145 8C. 1H NMR: dH
9.63 (br d, 1H, J ˆ 7:0 Hz), 8.62 (br s, 114), 7.91 (br d, 1H,
J ˆ 9:0 Hz), 7.69 (m, 1H), 7.28 (m, 1H). 19F NMR: dF
À61.63 (s).
3.2.1. (E)-3-Chloro-1,1,1-trifluoro-4-(2-pyridinylamino)-
3-buten-2-one (3a)
This was synthesized in 87% yield as described above for
enaminone 3b. Compound 3a: white crystals (mp 135±
136 8C). 1H NMR: dH 9.09 (d, 1H, J ˆ 12:0 Hz), 8.38
(dm, 1H, J ˆ 4:4 Hz), 7.96 (br d, 1H, J ˆ 8:1 Hz), 7.73
(m, 1H), 7.11 (m, 1H), 6.99 (d, 1H, J ˆ 8:1 Hz). 19F NMR:
dF À68.40 (s). Anal. Calcd. for C9H6ClF3N2O: C, 43.14; H,
2.41; N, 11.18. Found: C, 43.22; H, 2.40; N, 11.29.
Acknowledgements
We thank Prof. V.P. Kukhar for helpful discussion and Mr.
I.S. Kruchok for the experimental assistance.
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