Synthesis and Properties of Polyfunctional Cyclic β-Alkoxy-α,β-Unsaturated Ketones Based on 4-Methylene-1,3-dioxolanes

Article abstract of DOI:10.1002/ejoc.201800786

New CCl₃- and CF₃-substituted enones, bearing additional hidden hydroxymethyl functions, were prepared by acylation of 4-methylene 1,3-dioxolanes. The synthesized enones are interesting building blocks for agrochemical and medicinal chemistry research. The reactivity of synthesized enones with various amines was studied, and enaminones 13 and 14 were obtained under NH₃ interaction; the reaction with aliphatic primary amines afforded enaminones 17 in high yields as equilibrium mixtures of E and Z isomers. The reaction of fluorinated enone 9c with anilines afforded a mixture of products, including non-aromatic heterocyclic compounds 25 and 26 bearing the CF₃ group as well as furan 27 with CF₃ and amino functions at positions 5 and 3, respectively. The hydrolysis of enone 9c afforded cyclic compound 11.

Full text of DOI:10.1002/ejoc.201800786

DOI: 10.1002/ejoc.201800786
Full Paper
Fluorinated Synthons
Synthesis and Properties of Polyfunctional Cyclic ꢀ-Alkoxy-α,ꢀ-
Unsaturated Ketones Based on 4-Methylene-1,3-dioxolanes
Igor I. Gerus*[a] Olga A. Balabon,[a] Sergiy V. Pazenok,[b] Norbert Lui,[b] Ivan S. Kondratov,[a]
Karen V. Tarasenko,[a] Elena N. Shaitanova,[a] Viktor E. Ivasyshyn,[a] and Valery P. Kukhar[a]
Abstract: New CCl3- and CF3-substituted enones, bearing addi- mary amines afforded enaminones 17 in high yields as equilib-
tional hidden hydroxymethyl functions, were prepared by acyla- rium mixtures of E and Z isomers. The reaction of fluorinated
tion of 4-methylene 1,3-dioxolanes. The synthesized enones are enone 9c with anilines afforded a mixture of products, includ-
interesting building blocks for agrochemical and medicinal ing non-aromatic heterocyclic compounds 25 and 26 bearing
chemistry research. The reactivity of synthesized enones with the CF3 group as well as furan 27 with CF3 and amino functions
various amines was studied, and enaminones 13 and 14 were at positions 5 and 3, respectively. The hydrolysis of enone 9c
obtained under NH3 interaction; the reaction with aliphatic pri- afforded cyclic compound 11.
Introduction
its synthetic equivalent where aldehyde group is “hidden” as
ethoxyvinyl group (Figure 1).
Organofluorine compounds have a profound impact on the
modern Drug Discovery. For example in the years 2001–2011,
40 new fluorine containing substances were approved as drugs
and in general fluorine is present in about 25 % of drug mol-
ecules on the market.[1] Remarkable application of organofluor-
ine compounds are resulting from unique properties of fluor-
ine/fluoroalkyl groups the introduction of which into the active
molecule often leads to enhanced binding interactions, meta-
bolic stability, changes in physical and chemical properties of
fluorinated compounds.[2]
Figure 1. Enone 1a as a synthetic equivalent of 4,4,4-trifluoro-3-oxobutanal.
While the first examples of enone 1a application were pub-
lished 30 years ago it is still extensively used in the synthesis
of diverse organofluorine compounds.[4]
CF3-group is one of the most popular fluoroalkyl groups
which present in numerous drugs and drug-candidates, agro-
chemicals and substances used in Material Science. Therefore
numerous synthetic methods to introduce CF3-group were de-
veloped.
Among them the approaches based on CF3-containing build-
ing blocks are of particular interest because often lead to a
selective formation of target molecules with certain arrange-
ment of trifluoromethyl substituent and other groups.[3]
For instance, CF3-containing ꢀ-dicarbonyl compounds (e.g.
ꢀ-diketones) are widely used for the synthesis of heterocycles,
bearing CF3-group in required position. The one of the simplest
CF3-containing ꢀ-dicarbonyl compound – 4,4,4-trifluoro-3-oxo-
butanal – is not stable however often enone 1a can be used as
Also there is a huge interest to other similar compounds of
general structure 1 bearing various polyfluoroalkyl groups as
well as other substitutions in α- and/or ꢀ-position.[5] These com-
pounds can be easily obtained by acylation of the correspond-
ing enol ethers (Scheme 1).[6] Also the method can be used to
synthesize compounds bearing CCl3-group instead of poly-
fluoroalkyl group (R = CCl3). Such enones are also valuable for
further synthesis of functionalized heterocyclic compounds
since trichloromethyl moiety is a widespread precursor for the
synthesis of carboxylic function.[7]
[a] Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry
and Petrochemistry, National Ukrainian Academy of Science,
Murmanska Str. 1, Kiev 02094, Ukraine
E-mail: igerus@hotmail.com
http://www.nas.gov.ua/EN/PersonalSite/Pages/default.aspx?PersonID=
0000002529
[b] Bayer AG,
Scheme 1. Classical synthesis of ꢀ-alkoxyvinyl polyhaloalkyl ketones 1.
Alfred-Nobel-Strasse 50, 40789 Monheim, Germany
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800786.
Among others compounds 1 bearing an additional func-
tional group in α- or ꢀ-position are of particular interest since
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they can be involved in further transformation to produce more Results and Discussion
complex/functionalized molecules.
1.1. Synthesis of Enones 9a–d
For example, previously we demonstrated synthesis of CF3-
and CCl3-γ-bromosubstituted enones 2a,b[8] as well as enamin-
one 3 and demonstrated their application for the preparation
of functionalized molecules as 4–6, as a result of selective sub-
stitution of bromine by S-, N- and P-nucleophiles (Scheme 2).[9]
Obtained compounds 4–6 were found to be convenient start-
ing materials for further heterocyclizations.[7a,9]
In order to synthesize enones 9, the starting compounds 4-
methylene-1,3-dioxolanes 8a,b were prepared by literature pro-
cedure in 71–81 % common yields by a convenient two-step
protocol from epichlorohydrin (Scheme 4).[10] Next, compounds
8a,b were acylated by trifluoroacetic anhydride or trichloro-
acetyl chloride in the presence of pyridine affording the corre-
sponding enones 9a–d in moderate to high yields (Scheme 4,
Table 1). While fluorinated enones 9a,c are relatively stable and
can be stored at +4 °C for months without changes chloro-
containing enones 9b,d demonstrate spontaneous decomposi-
tion within several weeks at +4 °C which accompanied with
their darkening. Enone 9d was shown to be the most unstable.
Scheme 2. Bromination of ꢀ-alkoxyvinyl trifluoroalkyl ketones 3.
At the same time application of the similar methodology to
substitute bromine with various O-nucleophiles is challenging.
Thus, bromine substitution by acetate in CF3-enone 2a and the
synthesis of O-acetylated enone 7a (R1 = Ac) was described
previously.[7b] At the same time our own attempts to synthesize
compounds like 7a (R1 = Alk) by substitution of Bromine in
enone 2a using such O-nucleophiles as methanol and benzyl
alcohol in the presence of a base failed. Different conditions
were tried using various bases (e.g. K2CO3, Py, MeONa, DBU),
solvents (e.g. DMF, MeOH, THF, CH2Cl2) and temperature
(0–100 °C) but in all the cases complex mixtures were formed.
In order to develop an alternative approach to enone 7 ana-
logues we considered an alternative approach by acylation of
available 4-methylene-1,3-dioxolanes 8 to synthesize enones
9a,b. As enones 7 (R1 = H) compounds 9 are synthetic equiva-
lent of γ-hydroxy-ꢀ-diketone 10. However in enones 9 γ-
hydroxy- and ꢀ-carbonyl function are “hidden” as part of meth-
ylene-1,3-dioxoalne moiety (Scheme 3).
Scheme 4. Synthesis of enones 9a–d.
Table 1. Synthesis of enones 9a–d: starting materials and yields.
Entry
Starting material
Product
X
R1
Yield [%]
1
2
3
4
8a
8a
8b
8b
9a
9b
9c
9d
F
Cl
F
H
H
CH3
CH3
73
71
71
60
Cl
We also investigated the hydrolysis of obtained enones 9c,d.
The reaction was performed by stirring it with water without
any alkali or acid catalyst at room temp. for 2–3 days. In the
cases of compound 9c instead of expected diketone 10a, the
product 11 was obtained in moderate yield (Scheme 5). In con-
trast to fluorinated enone 9c, the hydrolysis of trichloromethyl-
containing enone 9d afforded complex mixture of unidentified
products as dark tarry material.
Scheme 5. Hydrolysis of enone 9c.
Scheme 3. Enones 7a,b, and 9a,b as synthetic equivalents of diketone 10.
Retrosynthetic approach to compounds 9a,b from methylene dioxolanes 8.
1.2. Reactions of Compounds 9a–d with Ammonia.
Reactions of 9c with Primary Aliphatic Amines
In this report we present simple synthetic approach to en-
ones 9a–d and particularities of their reactivity with various Our next step was to investigate the reaction of enones 9a,d
amines.
with ammonia and amines and compare the outcome of the
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reaction with previously described reaction of enones 1 with
N-nucleophiles.
Earlier the same reaction was investigated in details with en-
one 1a which readily reacts with amines to provide the corre-
sponding enaminones 12 in high yields (Scheme 6).[6a,11]
Table 2. Reaction of enone 9c with NH3: ratio of products depending on the
solvent.
Entry
Solvent
Product ratio[a] [%]
13a
14
1
2
3
4
5
Hexane
CH2Cl2
MeCN
MeCN/H2O (9:1)
H2O
60
80
90
99
40
20
10
< 1
0
100
[a] Determined based on 19F NMR spectra of reaction mixtures.
Scheme 6. Reaction of enone 1 with amines.
First, enones 9a,b were treated with ammonia in several sol-
vents (water, CH2Cl2, CH3CN, etc.). In all the cases the corre-
sponding enaminones 13a,b were formed in high yields
(Scheme 7).
Scheme 9. Reaction of enone 9d with NH3.
The proposed mechanism of compound 14 formation is pre-
sented on Scheme 10 and includes the addition of ammonia
to double bond of enone 9a, followed by transformation of
intermediate 15 into enaminone 16 bearing semiketal frag-
ment.[14] The elimination of either acetone or water from inter-
mediate 16 afforded enaminones 13a or 14, respectively.
Scheme 7. Reaction of enone 9a,b with ammonia.
It should be noted that non-halogenated analogs of the en-
aminones 13 were insufficiently described in literature and
were previously used for the synthesis of some monoamino
oxidase inhibitors like geiparvarin.[12]
Reaction of enone 1a with amines led to non-reactive eth-
anol elimination. At the same time reaction of enones 9a,b led
to liberation of reactive formaldehyde. As a result the amination
of enones 9a,b led to rather complex product mixture which is
difficult to purify. At the same time amination of the corre-
sponding acetonides 9c,d leads to liberation of less-reactive
acetone which can be easily removed under work-up. Therefore
for further investigation we mainly used enones 9c,d.
As expected enone 9c reacted with ammonia (as enone 9a)
giving enaminone 13a only in water solution. At the same time
when reaction was carried out with bubbling ammonia gas in
different solvents formation of additional unexpected product
14 was observed (Scheme 8, Table 2). The ratio of both
products depended on the solvent nature and obviously, both
high polarity and water presence decrease the percentage of
14. The latter was easily separated by hexane extraction from
more polar enaminone 13a.
Scheme 10. Proposed mechanism of compound 13a and 14 formation.
Also similar to interaction with ammonia the reaction of 9c
with several aliphatic primary amines afforded the correspond-
ing enaminones 17 in high yields, as expected (Scheme 11).
Scheme 11. Reaction 9c with primary amines.
Scheme 8. Reaction of enone 9c with NH3.
1.3. E/Z-Isomers of Enaminones 13a,b, 14, 17a–f
At the same time enaminone 13b was the only product in
the case of CCl3-containing enone 9d reaction with ammonia. Previously E/Z-isomerization behavior of compounds 12 was in-
We did not observe formation of cyclic enaminone analogous vestigated in details.[13] They were found to exist as a mixture
to 14 under different conditions (Scheme 9).
of E- and Z-isomers (when R1 = H), and the observed isomer
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ratio (by NMR and IR spectroscopy) mainly depends on solvent
polarity: in low polar solvents (e.g. hexane, CCl4) mainly (95 %)
Z-form is detected, stabilized by intramolecular hydrogen bond,
whereas in high polar solvents (DMF, DMSO, etc.) – as equilib-
rium mixture of mainly (75 %) two E-forms as a result of re-
stricted rotation around the C–N bond. When R1 = R2 = Alk,
compounds 12 exist in E-form only (Figure 2).[11]
Scheme 12. Reaction of enone 9c with secondary amines.
Figure 3. Intramolecular hydrogen bond formation in Z/E-isomers of enamin-
ones 17 and structures of enaminones 12a and 14 (see Table 3).
Table 3. The ratio of E-/Z-isomers of enaminones 17, 14 and 12a in various
solvents (see Figure 3).
Entry
Alk
Enaminone
Ratio of Z-/E-isomers,[a] [%]
[D6]DMSO
CDCl3
Z
E
Z
E
1
2
3
4
5
6
7
8
Me
Et
17a
17b
17c
17d
17e
17f
29
39
48
36
38
52
37
25
71
61
52
64
62
48
63
75
42
41
37
18
52
45
96
95
58
59
63
82
48
55
4
Figure 2. E,Z-isomers of compounds 12 and 13a,b.
iPr
tBu
cPr
cPen
–
The observed E-/Z-isomer ratio of compounds 13a,b, 14,
1
17a–f was estimated based on H and/or 19F NMR spectra and
also depended on the polarity of used solvent. In case of en-
aminones 13a,b we observed about 10 % of E-isomer in
[D6]DMSO. Again such a stability of Z-form is resulting from
intramolecular hydrogen bond formation between NH2- and
CO-groups. Such interaction is easily observed in 1H NMR spec-
tra as signal of NH at ≥ 10 ppm instead of unbound NH-proton
peak, typically observed at 7–8 ppm in analogous compounds.
In both E-13a,b and Z-13a,b it can be assumed also an addi-
tional H-bond formation between neighboring OH- and NH2-
groups (Figure 2).
Compounds 17 also exist as an equilibrium mixture of Z- and
E-isomers (Scheme 12, Table 2, entries 1–6). Remarkably, in this
case the isomer ratio depended only slightly on the solvent
polarity in contrast to the corresponding α-/ꢀ-unsubstituted en-
aminones 12 (Figure 2, above). Also for the most of compounds
17 E-isomer dominates in both solvents: CDCl3 and DMSO (see
Table 2). We suggest such behavior of enaminone 17 resulted
from hydroxymethyl group presence in ꢀ-position which can
form an additional intramolecular hydrogen bond with both
nitrogen and oxygen atoms in E-17 competing with hydrogen
bond in Z-17 (Figure 3). This intramolecular interaction dimin-
ishes influence of the solvent on the isomer ratio (Table 3).
14
–
12a[b]
5
[a] Determined by 1H and 19F NMR spectroscopy. [b] From the published
data.[11,13]
cant difference in behavior of structurally similar enaminones
17 and 14 or 12a is also in accordance with the assumption.
Thus, in compounds 17 intramolecular hydrogen bond forma-
tion (with participation of CH2OH-unit) is the main factor deter-
mining E/Z-isomer ratio and the solvent has minor influence in
contrast to cases of compounds 14 or 12a where E/Z-isomer
ratio is very sensitive to solvent nature.
1.4. Reaction of Enones 9c,d with Other Amines
Reaction of enone 9c with different secondary dialkylamines
(e.g. diethylamine, dibenzylamine, and morpholine) resulted
solely in formation of 4-dialkylamino-2-trifluoromethyl-2,5-di-
hydrofuran-2-ol 19a–c, which were isolated in moderate yields
(Scheme 12). Presumably the reaction takes place through the
corresponding intermediate enaminones 18 were detected in
We also studied the behavior of enaminone 14 in various the reaction mixture by NMR spectra but not isolated. In case of
solvents and found out that the E-/Z-isomer ratios in CDCl3 and di-isopropylamine, no conversion was observed under different
DMSO are very similar to enaminone 12a bearing Me-group at conditions (room temperature for 1–7 days or at 80 °C for 1 h).
the Nitrogen (see Figure 3, Table 2, entries 7,8). Such a signifi- Easiness of cyclic product 19a–c formation can be explained by
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a rapid intramolecular cyclization of the intermediate enamin-
ones 18 (which exists as E-isomer only), due to close spatial
arrangement of CO and CH2OH functional groups in E-18.
Products 19a–c were shown to be stable in [D6]DMSO solu-
tion on prolonged standing (by 1H and 19F NMR spectra). Prod-
uct 19c was stable in pure form whereas 19a,b afforded to
complex mixtures of unidentified products. Remarkably when
compound 19c was dissolved in CDCl3, its slow conversion into
isomer 20 as a result of an intramolecular double C=C bond
migration (Scheme 13). The isomerization can be easily ob-
served by 19F NMR spectrum showed initially a singlet at
–85.03 ppm, which corresponded 19c, while on standing a new
singlet at –85.53 ppm appeared due to compound 20 forma-
tion. The detected signal ratio reached 0.83:0.17 after 3 days
(17 % conversion of 19c to 20 in CDCl3).
Figure 4. X-ray structure of compound 21.
21 and opened form 23 also explains dynamic isomerization
of cis-/trans-21. At the same time we did not observed any
characteristic signals of aldehyde 22 in the reaction mixture.
Scheme 13. Isomerization of dihydrofuran 19c into 20.
When an excess of morpholine (2.2 equiv.) was used in the
reaction with enone 9c on prolonged reaction time (7 days) at
room temperature, an unexpected tetrahydrofuran 21 forma-
tion was observed, along with previously detected products
19c and 20 (Scheme 14). Unfortunately, our attempts to obtain
products as 20 and 21 starting from enone 9c and diethyl-
amine or benzylamine under different conditions failed.
Scheme 15. Proposed mechanism of compound 21 formation.
The reaction of fluorinated enone 9c with anilines resulted
1
in a complex mixture of products. Based on 19F and H NMR
spectroscopic data analysis, the following forms were identified:
enaminones 24 (as mixture of E and Z-isomers, the characteris-
tic signals of enaminone fragment are very similar to N-alkyl-
containing analogs 17), two isomeric dihydrofurans compounds
Scheme 14. Reaction of enone 9c with excess of morpholine.
Compound 21 was isolated and purified by crystallization 25 and 26 (their spectroscopic characteristics are similar to
from benzene in moderate yield. It was shown by NMR that products 19a–c and 20, see above), and furan 27 with CF3-
in [D6]DMSO solution compound 21 existed as a mixture of and amino groups at 5th and 3d positions, correspondingly
1
diastereomers with ratio 1:2 and broadened signals in H, 19F (Scheme 16).
and 13C NMR spectra can be explained by its dynamic isomeri-
Compounds 25 and 26 formed in similar way as 19a–c and
zation. At the same time in solid compound 21 exists as trans-
isomer only that was unambiguously proved by X-ray analysis
(Figure 4).
20, respectively, while furan 27 is a result of compound 26
dehydroxylation. This compound can be easily detected in the
reaction mixture because of characteristic chemical shift of CF3
We suggest compound 21 is formed from 20 which probably group (–63 ppm), typical for 2-CF3-substituted furans.[14] as well
1
exists in the solution in equilibrium with ketoaldehyde form 22. as two singlets of furan ring protons at H NMR spectra in the
The latter can react with one more morpholine molecule giving field 8.6–8.7 and 7.1–7.2 ppm. Isomers 25 and 26 can be also
semiaminal 23 which undergoes further cyclization to its more easily distinguished by NMR spectroscopy. For instance, vinyl
stable tetrahydrofuran tautomer 21 (Scheme 15). Equilibrium of C=CH-proton of dihydrofuran 25g had the typical chemical shift
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Finally the interaction of trichloromethyl-containing enones
9b,d with some primary or secondary amines was studied and
was shown to proceeds in other way then in case of fluorinated
enone 9c. For instance, in the case of the reaction with methyl-
amine and dimethylamine the only products, isolated from the
reaction mixture in high yields, were derivatives of tetronic acid
30a,b (Scheme 17). Compounds 30a,b formation can be ex-
plained by intramolecular addition of hydroxymethyl function
to carbonyl group with the formation of intermediate cyclic
semiketals 29 and following haloform reaction under basic con-
ditions with CHCl3 liberation.[15]
Scheme 16. Reaction of enone 9c with Ar-amines.
1
at δ = 5.19 ppm in H NMR, whereas the vinyl C=CH-proton of
compound 26g has upfield shift to 4.87 ppm by the influence
of adjacent oxygen. In the 19F NMR spectrum of the reaction
mixtures corresponding signals of the CF3-groups were found
at: –82.51 ppm for 25g, –82.91 ppm for 26g. Presumably com-
pounds 26 are formed from 25 through the formation of imines
28. At the same time we did not observed the presence of
compounds 28 in NMR spectra of the reaction mixtures.
The reaction outcome was found to be sensitive to para-
substituent in aniline structure (see Supporting Information,
Table S1). It can be concluded that in the case of electron-
withdrawing substituents the percentage of dihydrofurans 25
and 26 is higher than in the case of electron-donor groups.
Such observation can be explained by destabilization of
hydrogen bond between NH- and OH-groups in enaminones
24 due to electron-poor character of aromatic ring. This makes
favorable unbound OH-group attack on carbonyl group with
formation of 25 and its further isomerization to 26. On the
other hand, anilines bearing electron-withdrawing groups react
much slowly because of law NH2-group nucleophilicity. For in-
stance, in the case of para-nitroaniline, the starting enone was
the component in the reaction mixture even after 8 days at
room temp.
In the case of the reaction with anilines bearing electron-
donor substituents the corresponding enaminones 24 were iso-
lated and shown to be stable compounds in solid state. For
instance, compound 24f was characterized as a mixture of E-
and Z-isomers by 1H and 19F NMR spectra after dissolving in
[D6]DMSO and immediate spectral analysis, while 13C NMR
spectrum was too complex for unambiguous signal assignment.
In other cases the ratio of components 24–27 in the reaction
mixture was determined based on 19F NMR results. Unfortu-
nately, all our attempts to isolate and characterize individual
heterocyclic compounds 25–27 were not successful.
Scheme 17. Reaction of enone 9b,d with amines.
Structural assignment of 30 was based on the identity of
their 1H and 13C NMR spectroscopic data and melting points
with the literature data for 30a.[16]
Conclusions
New polyfunctional cyclic ꢀ-alkoxy-α,ꢀ-unsaturated ketones
9a–d, bearing trifluoromethyl- and trichloromethyl- groups,
were synthesized by acylation of readily available 4-methylene-
1,3-dioxolanes 8a,b in high yield. Enones 9a–d are interesting
building blocks for agrochemical and medicinal chemistry re-
search. Amination and hydrolysis of the enones 9 led to differ-
ent products depending on both enone 9a–d and starting
amine structure. In cases of ammonia and aliphatic primary
amines, the expected enaminones (e.g. compounds 13 and 17)
while in the case of secondary amines and anilines with unex-
pected dihydrofurans (compounds 19, 20, 25, 26) and furan
derivatives (27) as a result of initial intramolecular attack of
CH2OH-unit on carbonyl group. In case of enaminones 17 E-/Z-
isomerization behavior is significantly different from previously
studied enaminones 12 due to participation of CH2OH-unit in
additional intramolecular hydrogen bond formation. Also CCl3-
enones 9b,d were shown to be less stable and produced more
complex reaction mixtures (including formation of products
without CCl3-group). Further application of enones 9a–d as a
precursor to new CF3- and CCl3-containing heterocycles by their
reaction with different binucleophiles is now underway.
Experimental Section
General Methods: All reagents were commercially available and
used as received. Solvents were purified according to standard pro-
cedures. Starting materials were purchased from Acros, Merck,
Fluka, and Enamine. Melting points are uncorrected. Characteriza-
tion of intermediates and final compounds was done using 1H, 13C,
19F NMR and IR spectroscopy. 1H NMR spectra were recorded on
Varian Unity Plus at 400 MHz and Bruker DRX-500 at 25 °C. Chemical
shifts are reported downfield from TMS (for 1H and 13C NMR) and
The influence of solvent nature on reaction behavior was
studied using p-CF3-aniline which is easy to observe by NMR
spectra (see Supporting Information, Table S2). It was found
that the decrease of solvent polarity (DMSO > MeCN > THF
> CCl4) is favorable for the dihydrofuran 25g formation and
subsequent C=C-double bond migration to 26g and further de-
hydroxylation to furan 27g.
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CCl3F (for 19F NMR), coupling constants are given in Hz. Multiplicity
is given as (s) for singlet, (br.s) for broad singlet, (d) for doublet, (t)
for triplet, (q) for quartet, (dd) for doublet of doublets, and (m) for
aqueous solution was evaporated in vacuo. The pure product was
obtained using the extraction with ethyl acetate from the residue.
As white needles, yield: 51.9 % (1.26 g), m.p. 40–41 °C. 1H NMR
multiplet. 13C NMR spectra were recorded at 125 MHz with the (500 MHz, [D6]DMSO): δ = 2.63 (d, 2J = 18.6 Hz, 1 H, Ha of CH2), 3.04
central peak of CDCl3, triplet (δ C = 77.23 ppm) as the internal
reference. 19F NMR spectra were recorded at 376.3 MHz using CFCl3
as internal signal. IR absorptions were recorded at Bruker Vertex 70
in CH2Cl2 and KBr, the absorptions are given in wave numbers
(cm–1). The progress of reactions was monitored by using TLC (silica
(d, 2J = 18.6 Hz, 1 H, Hb of CH2), 4.24 (d, 2J = 17.1 Hz, 1 H, Ha of
2
CH2), 4.28 (d, J = 17.1 Hz, 1 H, Hb of CH2), 8.06 (s, 1 H, OH) ppm.
19F NMR (376.3 MHz, [D6]DMSO): δ = –82.93 (s, CF3) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 43.1, 70.7, 100.0 (q, 2JC-F = 33.4 Hz), 122.5
1
(q, JC-F = 285.0 Hz), 209.5 ppm. IR (CH2Cl2): ν = 3546, 1775, 1192,
˜
gel 60 F254, Merck). Column chromatography was carried out on 1102, 1060 cm–1. IR (KBr): ν = 3420, 1772, 1181, 1116, 1063, 990,
˜
silica gel 60 (Merck, particle size 0.040–0.063 mm). Compounds 8a,b
808, 733, 630, 587 cm–1. C5H5F3O3 (170.09): calcd. C 35.31, H 2.96;
found C 35.51, H 2.79.
were obtained according to the literature procedures.[10]
General Procedure for the Preparation of Enones 9a–d: To a
solution of 4-methylene-1,3-dioxolane (17.0 g, 0.197 mol) or 2,2-
dimethyl-4-methylene-1,3-dioxolane (22.8 g, 0.197 mol) in 100 mL
of DCM was added 17.1 mL (17.1 g, 0.217 mol) of pyridine. To the
stirred reaction mixture cooled to 10–15 °C and was then added a
solution of trifluoroacetic anhydride (41.4 g, 0.197 mol) or trichloro-
acetyl chloride (35.8 g, 0.197 mol) in 50 mL DCM. The reaction mix-
ture was left to stand over 12 h at room temp. then diluted with
70 mL of hexane and washed twice with acidified water. The com-
bined organic phases were dried with MgSO4, filtered, and the sol-
vents were evaporated. The residue was purified by vacuum distilla-
tion.
General Procedure for the Preparation of Enaminones 13a,b
from Enones 9a–d: 5.1 mL (67.1 mmol) of 25 % aq. solution of NH3
was added to the solution of the corresponding enone 9a (8.1 g,
44.7 mmol), 9b (10.3 g, 44.7 mmol), 9c (9.4 g, 44.7 mmol) or 9d
(11.6 g, 44.7 mmol) of in 50 mL of acetonitrile under vigorous stir-
ring. The reaction mixture was stirred for 1 h at room temp. Then
the solvent was evaporated to obtain almost pure target enamin-
one which was purified by crystallization from water.
4-Amino-1,1,1-trifluoro-5-hydroxypent-3-en-2-one (13a): Yield
from 9a: 96.0 % (7.26 g), as yellow crystals, m.p. 110–111 °C; spectra
in [D6]DMSO: Z-isomer: (92.6 %): 1H NMR (500 MHz, [D6]DMSO): δ =
4.19 (d, 3J = 5.8 Hz, 2 H, CH2OH), 5.38 (s, 1 H, OH), 5.71 (t, 3J =
5.8 Hz, 1 H, =CH), 8.68 (br.s, 1 H, NH), 9.81 (br.s, 1 H, NH) ppm. 19F
NMR (376.3 MHz, [D6]DMSO): δ = –75.32 (s, CF3) ppm. 13C NMR
(E)-3-(1,3-Dioxolan-4-ylidene)-1,1,1-trifluoropropan-2-one (9a):
Yield: 71 % (30.2 g) as yellow liquid, b.p. = 66–68 °C (12 mm/Hg).
1H NMR (500 MHz, [D6]DMSO): δ = 5.04 (s, 2 H, CH2), 5.59 (s, 2 H,
CH2), 6.28 (s, 1 H, =CH) ppm. 19F NMR (376.3 MHz, [D6]DMSO): δ =
–76.86 (s, CF3) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 70.8, 89.6,
1
(125 MHz, [D6]DMSO): δ = 60.5, 82.7, 117.4 (q, JC-F = 291.0 Hz),
2
174.1, 174.2 (q, JC-F = 32.0 Hz) ppm. E-isomer (7.4 %): 1H NMR
3
1
2
(500 MHz, [D6]DMSO): δ = 4.61 (d, J = 5.8 Hz, 2 H, CH2OH), 5.42 (s,
99.6, 116.1 (q, JC-F = 291.7 Hz), 177.9, 178.6 (q, JC-F = 33.9 Hz)
3
1 H, OH), 5.73 (t, J = 5.8 Hz, =CH), 8.03 (br.s, 1 H, NH), 8.77 (br.s, 1
ppm. IR (CH Cl ): ν = 2896, 1701, 1610, 1313, 1204, 1150, 1093, 939
˜
2
2
H, NH) ppm. 19F NMR (376.3 MHz, [D6]DMSO): δ = –74.88 (s, CF3)
ppm. 13C NMR (125 MHz, [D6]DMSO): δ = too low intensity of the
signals. NMR spectra in CDCl3: Z-isomer (97.7 %): 1H NMR (500 MHz,
CDCl3): δ = 2.4–2.6 (br.s, 1 H, OH), 4.44 (s, 2 H, CH2OH), 5.32 (s, 1
H, =CH), 6.9–7.1 (br.s, 1 H, NH), 10.0–10.2 (br.s, 1 H, NH) ppm. 19F
NMR (376.3 MHz, CDCl3): δ = –77.62 (s, CF3) ppm. E-isomer (2.3 %):
1H NMR (500 MHz, CDCl3): δ = 4.82 (s, 2 H, CH2), 5.39 (s, 1 H, =CH)
ppm, the signals of OH and NH2 groups in E- and Z-isomers are
overlapped. 19F NMR (376.3 MHz, CDCl3): δ = –77.47 (s) ppm. IR
cm–1. C6H5F3O3 (182.10): calcd. C 39.58, H 2.77; found C 39.77, H
2.52.
(E)-1,1,1-Trichloro-3-(1,3-dioxolan-4-ylidene)propan-2-one (9b):
Yield: 60 % (27.4 g), as yellow needles, m.p. 64–65 °C. 1H NMR
(500 MHz, CDCl3): δ = 4.99 (s, 2 H, CH2), 5.43 (s, 2 H, CH2), 6.36 (s, 1
H, =CH) ppm. 13C NMR (125 MHz, CDCl3): δ = 70.5, 89.9, 96.5, 98.9,
174.7, 181.4 ppm. IR (CH2Cl2): ν = 2894, 1700, 1619, 1367, 1256,
˜
1146, 977, 905, 834 cm–1. C6H5Cl3O3 (231.46): calcd. C 31.14, H 2.18;
found C 31.33, H 2.01.
(KBr): ν = 3213, 2923, 1651, 1558, 1441, 1318, 1244, 1133, 770, 731
˜
(E)-3-(2,2-Dimethyl-1,3-dioxolan-4-ylidene)-1,1,1-trifluoroprop- cm–1. C5H6F3NO2 (169.10): calcd. C 35.51, H 3.58, N 8.28; found
an-2-one (9c): Yield: 73 % (30.2 g) as yellow liquid, b.p. = 69–71 °C
C 35.35, H 3.43, N 8.32.
1
(15 mm/Hg). H NMR (500 MHz, [D6]DMSO): δ = 1.56 (s, 6 H, 2CH3),
5.16 (s, 2 H, CH2), 6.15 (s, 1 H, =CH) ppm. 19F NMR (376.3 MHz,
4-Amino-1,1,1-trichloro-5-hydroxypent-3-en-2-one (13b): Was
obtained using standard procedure above starting from 9b or 9d.
Yield from 9b: 93 % (9.1 g), from 9d: 99 % (9.7 g), as yellow crystals,
m.p. 96–100 °C (with decomposition); in NMR spectra in CDCl3 only
[D6]DMSO): δ = –76.75 (s, CF3) ppm. 13C NMR (125 MHz, [D6]DMSO):
1
δ = 24.4, 70.8, 89.0, 116.2 (q, JC-F = 292.0 Hz), 117.5, 178.0, 178.5
2
(q, JC-F = 34.0 Hz) ppm. IR (CH2Cl2): ν = 2998, 1699, 1560, 1339,
˜
1
1203, 1149, 1077, 904 cm–1. C8H9F3O3 (210.15): calcd. C 45.72, H
4.32; found C 45.82, H 4.21.
Z-isomer was observed. H NMR (500 MHz, CDCl3): δ = 2.37 (br.s, 1
H, OH), 4.45 (s, 2 H, CH2), 5.65 (s, 1 H, =CH), 6.76 (br.s, 1 H, NH), 9.59
(br.s, 1 H, NH) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 61.8, 81.7,
97.0, 169.6, 181.6 ppm. 13C NMR spectra in [D6]DMSO: Z (93.9 %):
1H NMR (500 MHz, [D6]DMSO): δ = 4.19 (d, 3J = 5.4 Hz, 2 H, CH2),
(E)-1,1,1-Trichloro-3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-
propan-2-one (9d): Yield: 71 % (36.3 g), as yellow needles, b.p. =
140 °C (0.5 mm/Hg). Enone 9d can be crystallized from hexane, m.p.
40–42 °C. 1H NMR (500 MHz, CDCl3): δ = 1.57 (s, 6 H, 2CH3), 5.12 (d,
3
5.68 (t, J = 5.4 Hz, 1 H, =CH), 5.69 (s, 1 H, OH), 8.36 (br.s, 1 H, NH),
9.36 (br.s, 1 H, NH) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 60.9,
4
4J = 1.5 Hz, 2 H, CH2), 6.30 (t, J = 1.5 Hz, 1 H, =CH) ppm. 13C NMR
79.9, 97.5, 173.2, 179.0 ppm. E (6.1 %): 1H NMR (500 MHz,
(125 MHz, CDCl3): δ = 25.05, 70.60, 88.97, 96.16, 116.15, 175.24,
3
[D6]DMSO): δ = 4.60 (d, J = 4.9 Hz, 2 H, CH2), 5.68 (br.s, 1 H, OH),
181.25 ppm. IR (CH2Cl2): ν = 2998, 1696, 1608, 1389, 1219, 1096,
˜
5.79 (s, 1 H, =CH), 7.76 (br.s, 1 H, NH), 8.59 (br.s, 1 H, NH) ppm. 13C
NMR (125 MHz, [D6]DMSO): δ = too low intensity of the signals. IR
(CH Cl ): ν = 3608, 3457, 1637, 1600, 1537, 830 cm–1. IR (KBr): ν =
843 cm–1. C8H9Cl3O3 (259.52): calcd. C 37.03, H 3.50; found C 37.28,
H 3.27.
˜
˜
2
2
5-Hydroxy-5-(trifluoromethyl)dihydrofuran-3(2H)-one (11): En-
3373, 3286, 2899, 2829, 1646, 1532, 1407, 1323, 1096, 1050, 810,
one 9c (3.0 g, 14.28 mmol) was mixed with 15 mL of water. The 742, 664 cm–1. C5H6Cl3NO2 (218.47): calcd. C 27.49, H 2.77, N 6.41;
mixture was stirred in 2–3 d giving the homogeneous solution. The
found C 27.29, H 2.63, N 6.56.
Eur. J. Org. Chem. 2018, 3853–3861
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3859
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Reaction of Enone 9c with NH3 (Gas): NH3 was bubbled through
the solution of enone 9c (1.87 g, 8.9 mmol) in 10 mL of hexane for
4.43 (s, 1 H, =CH), 4.52 (d, 2J = 12.7 Hz, 1 H, Ha of CH2), 4.67 (d, 2J =
12.7 Hz, 1 H, Hb of CH2), 7.26 (s, 1 H, OH) ppm. 19F NMR (376.3 MHz,
5 min. The reaction mixture was stirred for 1 h and then the solvent [D6]DMSO): δ = –82.64 (s, CF3) ppm. 13C NMR (125 MHz, [D6]DMSO):
2
1
was evaporated. The crude mixture was washed with hot hexane δ = 47.2, 65.4, 70.9, 87.8, 106.9 (q, JC-F = 32.9 Hz), 123.3 (q, JC-F
=
for 2 times giving a crude mixture of compounds 14 and 13a. The
product 14 was crystallized from hexane. The yield is 28 % (0.52 g).
The rest is containing almost pure enaminone 13a, which can be
additionally purified by crystallization from water. The yield is
69.8 % (1.05 g). The reaction in other solvents was carried out using
the same approach (for the ratio of products see Table 2, main text).
286.7 Hz), 153.2 ppm. IR (KBr): ν = 3337, 3132, 2963, 2881, 1645,
˜
1406, 1319, 1269, 1165, 1086, 955, 866, 765 cm–1. IR (CH2Cl2): ν =
˜
3574, 2972, 2864, 1641, 1451, 1270, 1181, 1121, 1089 cm–1. In NMR
spectra in CDCl3 the step-by-step isomerization of compound 19c
to 20 was observed. After 3 d the percentage of 20 was ca. 17 %.
1H NMR (500 MHz, CDCl3): δ = 2.66 (br.d, 2J = 17.7 Hz, 1 H, Ha of
CH2), 2.84 (br.d, 2J = 17.7 Hz, 1 H, Hb of CH2), 2.95 (m, 4 H, NCH2CH2),
3.74 (m, 4 H, OCH2CH2), 3.93–4.02 (br.s, 1 H, OH), 4.27 (m, 1 H, =CH)
ppm. 19F NMR (376.3 MHz, CDCl3): δ = –85.00 (s, CF3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 47.7, 66.2, 72.1, 87.8, 107.7 (q, 2JC-F = 34.4 Hz),
3-(2,2-Dimethyloxazolidin-4-ylidene)-1,1,1-trifluoropropan-2-
one (14): As yellow crystals, m.p. 40–42 °C.; in NMR spectra in CDCl3
1
only Z-isomer was observed. H NMR (500 MHz, CDCl3): δ = 1.55 (s,
6 H, 2CH3), 4.80 (s, 2 H, CH2), 5.36 (s, 1 H, =CH), 10.3 (br.s, 1 H, NH)
1
123.0 (q, JC-F = 287.2 Hz), 154.3 ppm. C9H12F3NO3 (239.19): calcd.
ppm. 19F NMR (376.3 MHz, CDCl3): δ = –77.23 (s, CF3) ppm. 13C NMR
C 45.19, H 5.06, N 5.86; found C 45.32, H 4.97, N 6.07.
1
(125 MHz, CDCl3): δ = 27.2, 71.3, 80.2, 98.7, 117.5 (q, JC-F
=
288.2 Hz), 164.9, 177.4 (q, 2JC-F = 33.4 Hz) ppm; spectra in [D6]DMSO:
Z-isomer (62.5 %): 1H NMR (500 MHz, [D6]DMSO): δ = 1.46 (s, 6 H,
2CH3), 4.81 (s, 2 H, CH2), 5.29 (s, 1 H, =CH), 10.75 (br.s, 1 H, NH)
ppm. 19F NMR (376.3 MHz, [D6]DMSO): δ = –75.27 (s, CF3) ppm. 13C
NMR (125 MHz, [D6]DMSO): δ = 26.4, 71.1, 78.3, 98.8, 117.4 (q,
1JC-F = 290.4 Hz), 164.1, 173.7 (br. q) ppm. E-isomer (38.5 %): 1H
NMR (500 MHz, [D6]DMSO): δ = 1.41 (s, 6 H, 2CH3), 5.06 (s, 2 H, CH2),
5.40 (s, 1 H, =CH), 10.35 (br.s, 1 H, NH) ppm. 19F NMR (376.3 MHz,
[D6]DMSO): δ = –75.28 (s, CF3) ppm. 13C NMR (125 MHz, [D6]DMSO):
δ = 26.8, 72.1, 79.8, 95.9, 117.6 (q, 1JC-F = 293.1 Hz), 167.2, 173.7 (br.
4-Morpholino-2-(trifluoromethyl)-2,3-dihydrofuran-2-ol (20):
The compound was observed in solutions, but wasn't isolated as
individual compound because of low stability. It was observed 17 %
after 3 d standing in CDCl3. 19F NMR (376.3 MHz, CDCl3): δ = –85.54
(s, CF3) ppm.
4,5-Dimorpholino-2-(trifluoromethyl)tetrahydrofuran-2-ol (21):
To the solution of 3 g (14.28 mmol) enone 9c in 10 mL of aceto-
nitrile was added morpholine 3.72 g (42.83 mmol). The reaction
mixture was stirred for 1 h and then stand for 3 d, the solvent was
evaporated and purification by crystallization from benzene gave
21 as white crystals. Yield: 50 % (2.23 g), m.p. 151–153 °C (with
decomp). 1H NMR (500 MHz, [D6]DMSO): δ = 1.98 (m, 1 H, NCH2CH2),
2.13 (m, 0.67 H, NCH2CH2), 2.38 (m, 2.33 H, NCH2CH2), 2.63 (m, 4 H,
NCH2CH2), 2.76 (m, 2 H, CH2), 3.00 (m, 0.33 H, CH), 3.14 (m, 0.67 H,
q) ppm. IR (CH2Cl2): ν = 2992, 1645, 1564, 1324, 1108, 853 cm–1
.
˜
C8H10F3NO2 (209.17): calcd. C 45.94, H 4.82, N 6.70; found C 45.82,
H 4.67, N 6.83.
General Procedure for the Preparation of Enaminones 17a–f: To
the solution of enone 9c (1 g, 4.76 mmol) in 10 mL acetonitrile was
added the corresponding amine (5.71 mmol). The reaction mixture
was stirred for 1 h, and then the solvent was evaporated to obtain
pure enaminone 21 which did not require further purification. All
the spectroscopic data and other physical chemical properties are
presented in Tables S3–S5.
3
CH), 3.55 (m, 8 H, OCH2CH2), 4.69 (d, J = 7.6 Hz, 0.67 H, CH), 4.78
3
(d, J = 7.3 Hz, 0.33 H, CH), 7.18 (br.s, 0.67 H, OH), 7.25 (br.s, 0.33 H,
OH) ppm. 19F NMR (376.3 MHz, [D6]DMSO): δ = –82.86 (s, 0.33, CF3),
–82.73 (s, 0.67, CF3) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 36.4,
36.5, 47.6, 47.9, 51.4, 51.7, 60.3, 61.9, 66.1, 66.2, 66.3, 66.4, 97.87 (q,
2
1
2JC-F = 32.4 Hz), 98.09 (q, JC-F = 32.0 Hz), 123.25 (q, JC-F ca.
1
286.6 Hz), 123.20 (q, JC-F ca. 286.6 Hz) ppm. IR (KBr): ν = 3239,
˜
General Procedure for the Synthesis of Compounds 19a–c: The
corresponding secondary amine was added to the solution contain-
ing 3 g (14.28 mmol) of enone 9c in 10 mL of acetonitrile. The
reaction mixture was stirred for 12 h, then the solvent was removed
in vacuo. The residue was then purified by column chromatography
on silica gel (ethyl acetate: hexane = 1:4).
2959, 2862, 1458, 1305, 1268, 1169, 1114, 1015, 900, 871,
689 cm–1. C13H21F3N2O4 (326.31): calcd. C 47.85, H 6.49, N 8.58;
found C 48.06, H 6.32, N 8.72.
General Procedure for the Monitoring the Influence of the Sub-
stituent at p-Position on the Reaction of Enone 9a with Aryl-
amines: To a solution enone 9a (1 g, 4.76 mmol) in 10 mL aceto-
nitrile was added the corresponding amine (4.76 mmol). The reac-
tion mixture was stirred for 5 min, and then the sample (0.2 mL)
4-(Diethylamino)-2-(trifluoromethyl)-2,5-dihydrofuran-2-ol
(19a): As brown oil, 36.6 %. 1H NMR (500 MHz, [D6]DMSO): δ = 1.04
3
3
was evaporated and the residue was dissolved in [D6]DMSO. 1H, 19
F
[t, J = 7.1 Hz, 6 H, 2(CH2CH3)], 3.01 [q, J = 7.1 Hz, 4 H, 2(CH2CH3)],
4.07 (s, 1 H, =CH), 4.52 (d, 2J = 12.0 Hz, 1 H, Ha of CH2), 4.66 (d, 2J =
12.0 Hz, 1 H, Hb of CH2), 6.3–8.0 (br.s, 1 H, H) ppm. 19F NMR
(376.3 MHz, [D6]DMSO): δ = –82.78 (s, CF3) ppm. C10H16F3NO2
(239.24): calcd. C 50.21, H 6.74, N 5.85; found C 50.43, H 6.50,
N 6.02.
NMR s were measured in order to monitor the reaction and to study
the influence of the substituent at p-position of aniline on its
progress (see Table S1).
1,1,1-Trifluoro-5-hydroxy-4-(4-methoxyphenylamino)pent-3-en-
2-one (24f): Spectra in [D6]DMSO: Z-isomer (32 %): 1H NMR
3
4-(Dibenzylamino)-2-(trifluoromethyl)-2,5-dihydrofuran-2-ol
(19b): As brown oil, 41.3 %, 1H NMR (500 MHz, [D6]DMSO): δ = 4.25
[s, 4 H, 2(CH2Ph)], 4.30 (s, 1 H, =CH), 4.65 (d, 2J = 12.5 Hz, Ha of CH2),
(500 MHz, [D6]DMSO): δ = 3.78 (s, 3 H, OCH3), 4.21 (d, J = 6.0 Hz,
3
2 H, CH2), 5.67 (t, J = 6.0 Hz, 1 H, =CH), 5.91 (s, 1 H, OH), 6.9 9 (d,
3
3J = 8.5 Hz, 2 H, Ar), 7.29 (d, J = 8.5 Hz, 2 H, Ar), 12.12 (s, 1 H, Ar)
2
3
ppm. 19F NMR (376.3 MHz, [D6]DMSO): δ = –75.07 (s, CF3) ppm; E-
4.78 (d, J = 12.5 Hz, 1 H, Hb of CH2), 7.22 (d, J = 7.1 Hz, 4 H, Ph),
3
3
isomer (68 %): 1H NMR (500 MHz, [D6]DMSO): δ = 3.79 (s, 3 H, OCH3),
7.27 (t, J = 7.1 Hz, 2 H, Ph), 7.35 (dd, J = 7.1 Hz, 4 H, Ph), 7.0 (br.s,
1 H, OH) ppm. 19F NMR (376.3 MHz), [D6]DMSO): δ = –82.85 (s, CF3)
ppm. C18H17F3NO2 (336.33): calcd. C 64.28, H 5.09, N 4.16; found C
64.39, H 5.07, N 4.32.
3
3
4.81 (d, J = 5.1 Hz, 2 H, CH2), 5.22 (s, 1 H, OH), 6.03 (t, J = 5.1 Hz,
1 H, =CH), 7.03 (d, 3J = 8.5 Hz, 2 H, Ar), 7.21 (d, 3J = 8.5 Hz, 2 H, Ar),
9.93 (s, 1 H, NH) ppm. 19F NMR (376.3 MHz, [D6]DMSO): δ = –74.95
(s, CF3) ppm.
4-Morpholino-2-(trifluoromethyl)-2,5-dihydrofuran-2-ol (19c):
As light yellow crystals, 53.1 %, m.p. 103–105 °C. 1H NMR (500 MHz,
General Procedure for the Monitoring the Influence of the Sol-
[D6]DMSO): δ = 2.93 (m, 4 H, NCH2CH2), 3.61 (m, 4 H, OCH2CH2), vent Polarity on the Reaction of Enone 9a with p-CF3-Aniline:
Eur. J. Org. Chem. 2018, 3853–3861
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3860 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[1] a) D. O'Hagan, J. Fluorine Chem. 2010, 131, 1071–1081; b) J. Wang, M.
Sánchez-Roselló, J. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A.
Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432–2506; c) Y. Zhou, J. Wang,
Z. Gu, S. Wang, W. Zhu, J. L. Acena, V. A. Soloshonok, K. Izawa, H. Liu,
Chem. Rev. 2016, 116, 422–518.
[2] a) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359–4369; b) A. Tressaud, G.
Haufe (Eds.), Fluorine and Health. Molecular Imaging, Biomedical Materials
and Pharmaceuticals, Elsevier, Amsterdam, 2008, pp. 553–778; c) I. Ojima
(Ed.), Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Black-
well, 2009, pp. 3–198; d) V. Gouverneur, K. Müller (Eds.), Fluorine in Phar-
maceutical and Medicinal Chemistry. From Biophysical Aspects to Clinical
Application, Imperial College Press, London, 2012, pp. 139–331; e) P.
Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applications,
2nd Completely Revised and Enlarged Edition, 2013, Wiley-VCH, Wein-
heim, pp. 1–379.
To a stirred solution of enone 9a (1 g, 4.76 mmol) in 10 mL of
corresponding solvent p-CF3-aniline (0.7 g, 4.76 mmol) was added
at room temp. The reaction mixture was stirred and then the sam-
ple (0.2 mL) was evaporated and the residue was dissolved in
[D6]DMSO. The reaction mixtures was monitored using 1H, 19F NMR
in 12 h, 48 h and 8 d to study the influence of the substituent at
p-position on the reaction (See Tables S1 and S2).
General Procedure for the Preparation of Compounds 30a,b: To
a solution of enone 9b (0.89 g, 3.85 mmol) or 9d (0.99 g, 3.85 mmol)
in 15 mL of acetonitrile was added the corresponding amine
7.71 mmol. The reaction mixture was stirred for 1 h and then the
solvent was removed in vacuo. The residue was purified by crystalli-
zation from hexane.
[3] J.-P. Bégué, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of
Fluorine, John Wiley & Sons, Inc., Hoboken, New Jersey, 2008, pp. 365.
[4] a) S. V. Druzhinin, E. S. Balenkova, V. G. Nenajdenko, Tetrahedron 2007,
63, 7753–7808; b) I. I. Gerus, R. X. Mironetz, I. S. Kondratov, A. V. Bez-
dudny, Y. V. Dmytriv, O. V. Shishkin, V. S. Starova, O. A. Zaporozhets, A. A.
Tolmachev, P. K. Mykhailiuk, J. Org. Chem. 2012, 77, 47–56; c) S. I. Vdo-
venko, I. I. Gerus, Y. I. Zhuk, V. P. Kukhar, G. V. Roschenthaler, Spectrochim.
Acta Part A 2014, 131, 94–101.
4-(Methylamino)furan-2(5H)-one (30a): As pale crystals, yield
from 9b: 63.9 % (0.28 g), m.p. 180 °C. 1H NMR (500 MHz, [D6]DMSO):
δ = 2.71 (d, 3J = 4.3 Hz, 3 H, CH3), 4.50 (s, 1 H, =CH), 4.60 (s, 2 H,
CH2), 7.44 (br.s, 1 H, NH) ppm. 13C NMR (125 MHz, [D6]DMSO): δ =
30.6, 66.8, 78.14, 169.7, 174.7 ppm. C5H7NO2 (113.12): calcd. C 53.09,
H 6.24, N 12.38; found C 53.31, H 6.02, N 12.57.
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4-(Dimethylamino)furan-2(5H)-one (30b): As pale crystals, yield
from 9d: 88.5 % (0.43 g), m.p. 63–65 °C. H NMR (500 MHz, CDCl3):
δ = 2.88 (s, 6 H, 2CH3), 4.52 (s, 1 H, =CH), 4.65 (s, 2 H, CH2) ppm.
13C NMR (125 MHz, CDCl3): δ = 38.8 (br.s), 40.1 (br.s), 66.9, 81.1,
169.2, 175.5 ppm. C6H9NO2 (127.14): calcd. C 56.68, H 7.13, N 11.02;
found C 56.81, H 6.98, N 11.26.
1
X-ray Crystal Structure Analysis for 21
Formula C13H21F3N2O4, M 326.32, monoclinic, space group P21/n,
a = 10.1676(4), b = 14.4938(5), c = 10.8422(4) Å, ꢀ = 107.367(2), V =
1524.94(10) Å3, Z = 4, dc = 1.421 g cm–3, μ = 0.128 mm–1, F(000) =
688, crystal size ca. 0.08 × 0.08 × 0.30 mm. All crystallographic
measurements were performed at 173 K on a Bruker Smart Apex II
diffractometer operating in the ω and ꢁ scans mode. The intensity
data were collected within the range of 2.41 ≤ θ ≤ 28.8° using Mo-
Kα radiation (λ = 0.71078 Å). The intensities of 16494 reflections
were collected (3916 unique reflections, Rmerg = 0.0496).
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Acknowledgments
The authors thank Enamine Ltd. (Kiev) for technical and State
Fund of Fundamental Research of Ukraine (grant F73/18-2017)
for financial support.
[16] a) T. Momose, N. Toyooka, T. Nishi, Y. Takeuchi, Heterocycles, 1988, 27,
1907; b) N. Lui, J. D. Heinrich, (Bayer CS, DE) US US2011054182A1, 2011.
Keywords: Enones · Acylation · Enaminones · Amination ·
Fluorinated compounds
Received: May 22, 2018
Eur. J. Org. Chem. 2018, 3853–3861
www.eurjoc.org
3861
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim