Domino transformations of gem-trifluoroacetyl(bromo)alkenes under the action of secondary amines

Article abstract of DOI:10.1002/ejoc.200700606

2-Bromo-3-arylpropenyl trifluoromethyl ketones underwent aza-Michael/hydroxyalkylation domino reactions triggered by secondary amines to give unexpectedly 2-amino-1-trifluoromethyl indenols in good yields. The process was found to involve the intermediate

Full text of DOI:10.1002/ejoc.200700606

FULL PAPER
DOI: 10.1002/ejoc.200700606
Domino Transformations of gem-Trifluoroacetyl(bromo)alkenes under the
Action of Secondary Amines
Alexander Yu. Rulev,*[a] Igor A. Uchakov,[a] Valentin G. Nenajdenko,[b]
Elisabeth S. Balenkova,[b] and Mikhail G. Voronkov[a]
Keywords: Enones / Nucleophilic substitution / Domino reactions
2-Bromo-3-arylpropenyl trifluoromethyl ketones underwent
aza-Michael/hydroxyalkylation domino reactions triggered
by secondary amines to give unexpectedly 2-amino-1-trifluo-
romethyl indenols in good yields. The process was found to
involve the intermediate formation of captodative amino-
alkenes. Treatment of 2-bromo-3-thienyl derivatives with the
same nucleophiles afforded the captodative trifluoroacetyl-
(amino)alkenes. The indenols obtained in this reaction can
be converted into the corresponding indanones by acid hy-
drolysis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
the chemistry of, in general, α,β-unsaturated trifluorometh-
yl ketones and, in particular, push–pull trifluoromethyl
aminoenones was strongly developed last decade and is well
documented.[5]
Introduction
Captodative carbonyl-containing aminoalkenes have in-
creasing interest to synthetic organic chemists.[1] Their at-
traction is caused by remarkable and specific reactivity that
is different from simple enamines and α,β-unsaturated alde-
hydes, ketones, and esters. These unique kinds of enamines
have been used as versatile building blocks in the synthesis
of various biologically important heterocycles and analogs
of natural substances. It is well known that the introduction
of fluorine atoms in organic molecules often produces dra-
matic modifications of the chemical properties and bio-
logical activity of parent compounds.[2] Thus, trifluorome-
thylated derivatives are of great interest in various fields of
applications as shown, for example, by the number of CF3-
containing drugs.[3] That is why the development of new
fluorinated building blocks is always required. Recently,
considerable attention has been given to the fluorine-bear-
ing derivatives of enamines.[4] In the context of our going
interest in the chemistry of captodative aminoalkenes and
in search of the synthesis of fluorinated building blocks and
analogs of bioactive compounds, we turned our attention
to the enamines bearing a trifluoroacetyl group at the gem
position. The symbiosis of the enamine and perfluoroacyl
moieties is of considerable theoretical, synthetic, and phar-
macological interest. To the best of our knowledge, this
type of compound has not yet been studied. In contrast,
The most straightforward route for the preparation of
captodative trifluoroacetyl(amino)alkenes is substitution of
a particular leaving group by an amino one. Because halide
ions are one of the best nucleophiles, the corresponding α-
halo-α,β-unsaturated trifluoromethyl ketones can serve as
key intermediates. Therefore, a retrosynthetic approach for
the target compounds considers the introduction of the
halogen atom at the α-position as the initial step, followed
by its nucleophilic substitution with a secondary amine as
the second step (Scheme 1). This strategy is universal and
very attractive because of its experimental simplicity and
availability of the starting compounds. Previously, this
methodology was successfully applied to the synthesis of
various captodative aminoalkenes containing a carbonyl-,
formyl-, or alkoxycarbonyl functional group[1,6] as an elec-
tron-withdrawing group and including derivatives having a
slow basic tertiary amino group as well as a terminal double
bond.[7] It is interesting to remark that only the β-alkoxy
group has been regiospecifically substituted with secondary
or primary amines in their reactions with β-butoxy-α-bro-
movinyl trifluoromethyl ketone.[5e] In this paper we describe
our synthetic efforts to synthesize captodative trifluoroace-
tyl(amino)alkenes.
[a] A. E. Favorsky Institute of Chemistry, Siberian Branch of the
Russian Academy of Sciences,
1, Favorsky Str., Irkutsk 664033, Russia
Fax: +7-3952-419346
E-mail: rulev@irioch.irk.ru
[b] Department of Chemistry, Moscow State University,
119899 Moscow, Russia
Scheme 1. Retrosynthetic route to captodative trifluoroacetyl(ami-
no)alkenes.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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A. Yu. Rulev et al.
FULL PAPER
fact presents as a Michael addition–substitution–elimi-
nation domino sequence, Ad–SN–E.[11] Consequently, an in-
crease in the EWG acceptor ability should be favorable to
the first step of the reaction Ϫ the aza-Michael addition.
The 13C NMR chemical shift differences between adjacent
olefinic carbon atoms can serve as a reliable parameter of
double bond polarization.[12] On the basis of the data in
Table 1, it was expected that bromoalkenes bearing a tri-
fluoroacetyl group would be the most active Michael ac-
ceptors. Indeed, it was reported earlier that unsubstituted
trifluoromethyl alkenyl ketones are highly reactive species
toward nucleophilic addition reactions.[13]
Results and Discussion
The required starting materials Ϫ trifluoroacetyl(bromo)-
alkenes 3a–d Ϫ were prepared in high overall yields after a
two-step procedure involving the reaction of readily avail-
able trifluoromethyl alkenyl ketones 1a–d[8] with bromine in
anhydrous CHCl3, and subsequent dehydrobromination of
intermediate dibromo derivatives 2a–d by Et3N in dry ether
(Scheme 2).
Table 1. The relationship between the chemical shift differences
(Cβ–Cα) and the nature of the electron-withdrawing group of bro-
moalkenes.
Scheme 2. Reagents and conditions: (i) Br2, 0 °C, CHCl3; (ii) Et3N,
10 °C, Et2O.
Ketones 3a–d were identified as a single geometric iso-
mer. Their (Z) configuration was established by the con-
certed application of a 1H–1H 2D NOESY homonuclear
experiment and also a 1H–13C 2D HMBC heteronuclear ex-
periment for bromo derivatives 3c,d (Figure 1). In fact, the
spectrum of ketone 3c contains only one NOE peak be-
tween the resonance of the olefinic proton and the protons
of methoxy group in the 2-position, whereas no correlations
are seen between the proton of the CH= group and any
aromatic signals. The methoxy group in the 5-position has
NOE interactions with both the 4- and 6-aromatic protons.
The presence of a quite intensive cross peak between the
olefinic proton and the =C3–H proton of the thienyl moiety
was revealed in compound 3d. This fact led us to the con-
clusion that the bromine atom and aromatic (for 3c) or thi-
enyl (for 3d) moieties are arranged in a (Z) configuration.
The geometry of these ketones was elucidated also by com-
parison of the vicinal coupling constant between the car-
bonyl C atom and the olefinic proton (3JC–H = 6.0 and
5.2 Hz for compounds 3c and 3d, respectively). It is known
that this constant lie between 0 and 6 Hz for the s-cis isomer
and between 9 and 14 Hz for the s-trans isomer.[9] The ad-
ditional arguments have been received from the analysis of
their IR spectra: the intensity ratio observed for the C=O
and C=C stretching bands suggests a s-cis conformation of
the C=C–C=O fragment.[10]
Entry
R1
R2
∆ (δ Cβ – δ Cα)
1
2
3
4
5
6
4-MeOC6H4
Ph
thienyl
2,5-(MeO)2C6H3 CF3
Ph
Ph
CF3
CF3
CF3
33.21
30.30
26.80
25.82
H
Ph
24.32[14]
20.08[14]
We found that the reaction of bromoenones 3a–d with
secondary amines (2 equiv.) readily proceeds under mild
conditions (room temperature, without catalyst). Unfortu-
nately, attempts to prepare the target captodative trifluoro-
methyl(amino)alkenes in the case of enones 3a–c failed.
Surprisingly, the only isolated products, formed in good
yield, were indenols 4a–e (Scheme 3). Their structure was
confirmed by spectroscopic methods. The 1H NMR spectra
of indenols 4a–e show a singlet for the olefinic proton at δ
= 5.25–5.45 ppm. In the 13C NMR spectra of these com-
pounds, a signal for the carbonyl group is absent. Instead,
a quadruplet of a quaternary carbon atom joined to a CF3
moiety appears at δ = 83–86 ppm (J = 30 Hz). An alterna-
tive structure of 3-amino-substituted indenol was excluded
by additional NMR spectroscopic experiments. Thus, ac-
cording to the 2D NOESY NMR spectrum of 4d, there
are off-diagonal peaks between the olefinic proton and the
signals for both the MeO and NCH2 groups, which indi-
cates the α-position of the amino functionality.
It should be noted that the result depends on the nature
of the solvent. For example, whereas the reaction of ketone
3a with diethylamine in ethanol gives a complex mixture of
products, the use of ether or THF as solvent leads to the
formation of indenol 4a as a major (or single) product.
Indenols, as is well known, are an important type of or-
ganic compounds that attract the attention of both syn-
thetic and pharmaceutical chemists.[15] Despite this fact,
Figure 1. Relative stereochemistry of bromoenones 3c,d.
According to the classical scheme now generally ac- few methods have been proposed for the synthesis of these
cepted, the reaction of nucleophiles with haloalkenes bear- derivatives and, as a rule, transition-metal-catalyzed coup-
ing an electron-withdrawing group (EWG) at the gem posi- ling reactions have been employed. So, this reaction is very
tion does not proceed through direct substitution and in efficient for the preparation of functionalized 1-trifluoro-
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Domino Transformations of gem-Trifluoroacetyl(bromo)alkenes
Scheme 3. Reagents and conditions: HNR2, Et2O or THF, r.t.
methyl-1-indenols. However, when the reaction was carried hydroxyalkylation reaction of intermediates 6a–f leads di-
out with bromoenone 3d, the corresponding indenol deriva- rectly to final indenols 4a–f. The influence of the trifluoro-
tives were not obtained at all. It is known that the forma- methyl group on such a result is quite clear. The strong
tion of a five-membered ring condensed with thiophene electron-withdrawing character of the CF3 moiety activates
does not proceed very easily. To contrast to enones 3a–c, the carbonyl group and then favors the hydroxyalkylation
bromoketone 3d was treated with dipropylamine or dibu- reaction.
tylamine to give target captodative aminoalkenes 5a,b
(Scheme 3). The moderate yields of aminoalkenes 5a,b
probably can be explained by the side reactions (polymeri-
zation, hydrolysis, etc.) due to the instability of these deriva-
1
tives. According to H and 13C NMR spectra, these com-
pounds exist as a single isomer. The value of the vicinal
coupling constant between the carbon atom of the carbonyl
group and the olefinic proton (3JC–H = 5.7 Hz) as well as
NOE experiments led us to the conclusion that amino-
enones 5a,b have the same (Z) configuration as initial bro-
moenone 3d (Figure 2).
Scheme 4. Reaction cascade Ad–SN–E–cyclization.
To provide further support for the postulated scheme, we
monitored the reaction of ketones 3b,c with dibutylamine
and dipropylamine, respectively. In these cases, analysis of
the reaction mixtures has shown that the first three steps
were quite rapid reactions, whereas the cyclization reaction
was a limiting step. In fact, the amine hydrobromide pre-
cipitate appeared within some minutes of the start of the
reaction. Thus, when dibutylamine was treated with ketone
Figure 2. Relative stereochemistry of aminoenone 5a.
As we have mentioned, this reaction does not proceed 3b for 15 h at room temperature, a mixture (10:1) of capto-
through direct halogen substitution. On the basis of the re- dative aminoenone 6a and corresponding indenol 4c was
1
sults and known nucleophilic vinylic substitution in gem- recorded by H NMR spectroscopy. We obtained both the
activated haloalkenes, the following general sequence of 1H and 13C NMR spectra of intermediate 6a. The capto-
transformations can be proposed to explain this reaction dative nature of this aminoenone[14a] is supported by com-
cascade (Scheme 4). A complete interpretation of the reac- parison of the chemical shifts of the olefinic carbon atoms:
tion mechanism is hampered because possible intermediates the signal of the β atom is at higher field relative to that of
A and B were not isolated and their formation has not been the α atom (115.8 and 158.5 ppm, respectively). According
recorded. However, we can suggest that the first step of to 2D NMR spectra (NOESY and HMBC), the geometry
these domino transformations includes aza-Michael ad- of intermediate 6a is opposite to the configuration of
dition to initial substrate 3, further replacement of the halo- captodative aminoenone 5a and favorable to the cyclization
gen at the sp3 carbon atom of saturated ketone A, and eli- into indenol 4c. Thus, the signal of the carbonyl carbon
3
mination of the secondary amine to give the product of ipso atom appeared as a quartet of doublets with JC–H
=
2
substitution. Unfortunately, derivatives 5, 6a–e could not be 10.3 Hz and JC–F = 34.5 Hz, which indicates that amino-
1
isolated, but they could be detected by H and 13C NMR enone 6a has the configuration shown in Figure 3. During
1
spectroscopy of the crude reaction mixture. The following the reaction, we observed that in the H NMR spectra the
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A. Yu. Rulev et al.
FULL PAPER
singlet for the olefinic proton of derivative 6a (δ = converted into indanone 8 by treatment with a solution of
5.89 ppm) disappeared with the simultaneous appearance hydrochloric acid at room temperature over 2 h in an over-
of a singlet for the olefinic proton of indenol 4c (δ = all yield up to 68%.
5.25 ppm). In the 13C NMR spectrum, the quadruplet of
the carbonyl group of intermediate 6a was observed at δ
= 186.9 ppm. Its disappearance after some hours and the
appearance of the signal for the quaternary carbon atom
C(OH)CF3 as a quadruplet at δ = 83.0 ppm proved the
transformation of linear aminoenone 6a to cyclic derivative
4c. The same sequence of transformations was recorded by
NMR spectroscopy during the monitoring of the reaction
of ketone 3c with dipropylamine.
Conclusion
We achieved the one-pot synthesis of indenol derivatives
from easily available trifluoroacetyl(bromo)alkenes and sec-
ondary amines. Considering the importance of indenols as
useful building blocks in the synthesis of natural com-
pounds and their biological activity, we developed an ef-
ficient method for the synthesis of 1-trifluoromethyl-1-
indenols. We attributed this unexpected result to the very
easy intramolecular cyclization of intermediate captodative
trifluoroacethyl(dialkylamino)alkenes. The latter can be de-
tected in the reaction mixture and isolated in the case of β-
thienyl-substituted derivatives. The results obtained in this
study confirm our previous observations in the unpredict-
able chemistry of captodative carbonyl bearing enamines.
Further development of this methodology and detailed
studies of the properties of the captodative trifluoroacetyl-
(amino)alkenes and corresponding indenols are now in pro-
gress.
Figure 3. Relative stereochemistry of aminoenone 6a.
Moreover, we were fortunate to restrain the reaction at
the first step and recorded the aza-Michael adduct. It is
known that the N-trimethylsilyl derivatives of secondary
amines react as nucleophiles, and thus they were used to
determine the reaction mechanism.[16] We found that treat- Experimental
ment of enone 3a with trimethyl(diethylamino)silane under
General Remarks: 1H, 13C, 15N, and 19F NMR spectra were re-
corded with a Bruker AVANCE 400 MHz spectrometer for solu-
tions in CDCl3 or CD3CN. Chemical shifts (δ) in ppm are reported
microwave conditions produce aza-Michael adduct 7. In
1
fact, in the H NMR spectrum of the reaction mixture the
1
signals of compound 7 are observed only: δ = 0.99 (t, J =
7.1 Hz, CH3), 2.65 (q, J = 7.1 Hz, CH2), 4.87 (s, CH), 7.25–
by using residual chloroform (7.25 ppm for H and 77.20 ppm for
13C) or acetonitrile (1.94 ppm for 1H and 1.40, 118.60 ppm for 13C)
7.55 (m, C6H5) ppm; 19F NMR: δ = –58.23 ppm. So, the as internal references. The coupling constants (J) are given in
Hertz. The concerted application of 1H–1H 2D COSY[17] and
formation of silyl enol ether 7 may serve as strong proof
for the suggested mechanism (Scheme 5). These results once
more indicated that the reaction occurred through an aza-
Michael addition–substitution–elimination–hydroxylation
NOESY[18] homonuclear experiments as well as 1H–13C 2D
HSQC[19] and HMBC[20] heteronuclear experiments were used for
the distinction of the carbon and proton resonances in all cases.
The IR spectra were measured with a Specord IR-75 instrument.
The GC–MS analyses were performed with a Hewlett–Packard HP
sequence.
5971A instrument (EI, 70 eV). The silica gel used for flash
chromatography was 230–400 mesh. All reagents were of reagent
grade and were used as such or distilled prior to use. All the sol-
vents were dried according to standard procedures and freshly dis-
tilled prior to use. Trifluoromethyl alkenyl ketones 1a–d were pre-
pared as reported previously.[5b,8]
Scheme 5. Reagent and conditions: Me3SiNEt2, microwave.
General Procedure for the Bromination of Ketones 1a–d: Bromine
(0.8 g, 5 mmol) in CHCl3 (5 mL) was added dropwise over 30 min
into a stirred solution of the ketone (5 mmol) in CHCl3 (5 mL).
During the addition, the temperature was kept at +10 °C. The mix-
ture was then stirred at room temperature until the orange color
did not fade away. The solvent was evaporated and a light-yellow
solid appeared. The crude dibromo derivatives 2a–d were found
suitable for further transformation without any purification.
It is remarkable that indenols 4 exhibit properties of sim-
ple enamines; in particular, they are hydrolyzed to give the
corresponding carbonyl derivatives (Scheme 6). Thus, inde-
nols 4b,c obtained from ketone 3b and diethyl- and dibu-
tylamine, respectively (without purification), were easily
Triethylamine (0.5 g, 5 mmol) in anhydrous ether (10 mL) was
added dropwise over 5 min into a stirred solution of dibro-
moketone 2 (5 mmol) in Et2O (10 mL) at +10 °C. The mixture was
kept at room temperature overnight and filtered. After the solvent
was evaporated, α-bromoenones 3a–d were obtained either by dis-
tillation at reduced pressure (3a,b) or column chromatography
(3c,d).
Scheme 6. Reagents and conditions: H2O/HCl, r.t.
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Domino Transformations of gem-Trifluoroacetyl(bromo)alkenes
3-Bromo-1,1,1-trifluoro-4-phenyl-3-buten-2-one (3a): Yield 90%. CDCl3): δ = 12.31 (CH3), 44.22 (NCH2), 83.25 (q, J = 30.0 Hz, C-
Yellow liquid, b.p. 100(3) °C. IR (KBr): ν = 1592 (C=C), 1712
OH), 103.63 (CH=), 117.88, 122.11, 122.33, 122.97, 130.72 (CH
aryl), 124.84 (q, J = 283 Hz, CF3), 144.93 (C aryl), 152.42 (=C-N)
˜
1
(C=O) cm–1. H NMR (400.16 MHz, CDCl3): δ = 7.40–7.55 (m, 3
H), 7.90–8.00 (m, 2 H), 8.17 (s, 1 H) ppm. 13C NMR (100.61 MHz, ppm. 19F NMR (376.5 MHz, CDCl3): δ = –79.25 ppm. MS (EI):
CDCl3): δ = 116.04 (q, J = 291.4 Hz, CF3), 116.96 (=C-Br), 128.98,
131.54, 132.23 (CH aryl), 133.17 (C aryl), 147.26 (q, J = 3.8 Hz, C14H16F3NO (271.28): calcd. C 61.99, H 5.94, F 21.01, N 5.16;
m/z (%) = 271 (78) [M]+, 256 (100), 210 (17), 158 (18), 89 (33).
CH=), 175.91 (q, J = 35.3 Hz, C=O) ppm. 19F NMR (376.5 MHz,
CDCl3): δ = –69.35 ppm. MS (EI): m/z (%) = 280 (25) [M + 1]+, 278
(25) [M – 1]+, 209, 211 (32), 181, 183 (14), 102 (100). C10H6BrF3O
(279.06): calcd. C 43.04, H 2.17, Br 28.63, F 20.42; found C 42.87,
H 2.25, Br 28.19, F 20.31.
found C 62.07, H 6.01, F 20.67, N 5.01.
2-(Diethylamino)-6-methoxy-1-(trifluoromethyl)-1H-inden-1-ol (4b):
1H NMR (400.16 MHz, CDCl3): δ = 1.12 (t, J = 7.5 Hz, 6 H),
3.15–3.30 (m, 2 H), 3.35–3.50 (m, 2 H), 3.77 (s, 3 H), 5.34 (s, 1 H),
6.70 (dd, J = 2.4, 8.0 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 7.00 (d,
J = 2.4 Hz, 1 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 11.82
(CH3), 43.77 (NCH2), 55.44 (OCH3), 82.91 (q, J = 29.6 Hz, C-OH),
104.00 (CH=), 111.15 (C-7), 114.51 (C-5), 117.84 (C-4), 124.60 (q,
J = 285 Hz, CF3), 137.29 (C-9), 138.67 (C-8), 150.91 (=C-N),
3-Bromo-1,1,1-trifluoro-4-(4-methoxyphenyl)-3-buten-2-one
(3b):
Yield 86%. Pale yellow crystals, b.p. 142–143(1) °C, m.p. 45 °C. IR
(KBr): ν = 1585 (C=C), 1692 (C=O) cm–1. 1H NMR (400.16 MHz,
˜
CDCl3): δ = 3.85 (s, 3 H), 6.96 (d, J = 9.0 Hz, 2 H), 8.00 (d, J =
9.0 Hz, 2 H), 8.09 (s, 1 H) ppm. 13C NMR (100.61 MHz, CDCl3):
δ = 55.71 (OCH3), 113.94 (=C-Br), 114.53 (CH aryl), 116.14 (q, J
= 291.5 Hz, CF3), 125.51 (C aryl), 134.37 (CH aryl), 147.15 (q, J
= 3.7 Hz, CH=), 163.21 (Car-O), 176.20 (q, J = 35.0 Hz, C=O)
ppm. 19F NMR (376.5 MHz, CDCl3): δ = –69.00 ppm. MS (EI):
m/z (%) = 279 (2) [M – MeO + 1]+, 277 (2) [M – MeO – 1]+, 239,
241 (42), 132 (100), 89 (45). C11H8BrF3O2 (309.08): calcd. C 42.75,
H 2.61, Br 25.85, F 18.44; found C 42.76, H 2.71, Br 26.24, F
18.06.
155.66 (Car-O) ppm. 19F NMR (376.5 MHz, CDCl3):
–78.55 ppm.
δ =
2-(Dibutylamino)-6-methoxy-1-(trifluoromethyl)-1H-inden-1-ol (4c):
1H NMR (400.16 MHz, CDCl3): δ = 0.90 (t, J = 7.5 Hz, 6 H),
1.25–1.40 (m, 4 H), 1.45–1.60 (m, 4 H), 2.95–3.10 (m, 2 H), 3.50–
3.65 (m, 2 H), 3.70 (s, 3 H), 5.25 (s, 1 H), 6.65 (dd, J = 2.4, 8.0 Hz,
1 H), 6.73 (d, J = 8.0 Hz, 1 H), 6.96 (d, J = 2.4 Hz, 1 H) ppm. 13C
NMR (100.61 MHz, CDCl3): δ = 14.10 (CH3), 20.38, 29.40 (CH2),
50.50 (NCH2), 55.35 (OCH3), 83.00 (q, J = 29.6 Hz, C-OH), 103.50
(CH=), 111.20 (C-7), 113.90 (C-5), 117.10 (C-4), 125.11 (q, J =
285 Hz, CF3), 137.40 (C-9), 139.20 (C-8), 151.60 (=C-N), 155.66
3-Bromo-4-(2,5-dimethoxyphenyl)-1,1,1-trifluoro-3-buten-2-one (3c):
Yield 92%. Red crystals, m.p. 72 °C. IR (KBr): ν = 1570 (C=C),
˜
(Car-O) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –77.99 ppm. 15
NMR (40.55 MHz, CDCl3): δ = –304.5 ppm.
N
1
1695 (C=O) cm–1. H NMR (400.16 MHz, CDCl3): δ = 3.78 (s, 3
H), 3.84 (s, 3 H), 6.87 (d, J = 9.0 Hz, 1 H), 7.04 (dd, J = 9.0,
2.8 Hz, 1 H), 7.86 (d, J = 2.8 Hz, 1 H), 8.61 (s, 1 H) ppm. 13C
NMR (100.61 MHz, CDCl3): δ = 56.03, 56.52 (OCH3), 112.13 (CH
aryl), 114.85 (CH aryl), 116.05 (q, J = 291.8 Hz, CF3), 116.93 (=C-
Br), 120.01 (CH aryl), 122.43 (C aryl), 145.75 (q, J = 3.5 Hz, CH=),
153.08, 153.48 (Car-O), 176.14 (q, J = 34.9, 3J = 6.0 Hz, C=O)
ppm. 19F NMR (376.5 MHz, CDCl3): δ = –68.48 ppm. MS (EI):
m/z (%) = 340 (100) [M + 1]+, 338 (100) [M – 1]+, 307, 309 (72),
175 (93), 69 (47). C12H10BrF3O3 (339.11): calcd. C 42.50, H 2.97,
Br 23.56, F 16.81; found C 43.04, H 3.17, Br 23.55, F 16.57.
2-(Diethylamino)-4,7-dimethoxy-1-(trifluoromethyl)-1H-inden-1-ol
(4d): Yield 47%. Oil. IR (KBr): ν = 1680 (C=C), 3510 (OH) cm–1.
˜
1H NMR (400.16 MHz, CDCl3): δ = 1.16 (t, J = 7.0 Hz, 6 H),
3.15–3.30 (m, 2 H), 3.50–3.65 (m, 2 H), 3.82 (s, 3 H), 3.86 (s, 3 H),
4.43 (br. s, 1 H), 5.45 (s, 1 H), 6.46 (d, J = 8.8 Hz, 1 H), 6.76 (d, J
= 8.8 Hz, 1 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 12.45
(CH3), 44.66 (NCH2), 55.92, 56.32 (OCH3), 85.53 (q, J = 30.0 Hz,
C-OH), 99.11 (CH=), 105.94, 114.26, 122.33 (CH aryl), 125.30 (q,
J = 289 Hz, CF3), 135.16, 145.57, 150.16 (C aryl), 151.95 (=C-N)
ppm. C16H20F3NO3 (331.34): calcd. C 58.00, H 6.08, N 4.23; found
C 57.79, H 6.09, N 4.09.
3-Bromo-1,1,1-trifluoro-4-(2-thienyl)-3-buten-2-one (3d): Yield 66%.
Pale brown crystals, m.p. 34–35 °C. IR (KBr): ν = 1580 (C=C),
˜
1
1700 (C=O) cm–1. H NMR (400.16 MHz, CDCl3): δ = 7.25 (dd,
2-(Dipropylamino)-4,7-dimethoxy-1-(trifluoromethyl)-1H-inden-1-ol
(4e): Yield 74%. Oil. IR (KBr): ν = 1667 (C=C), 3500 (OH) cm–1.
J = 5.1, 3.9 Hz, 1 H), 7.72 (dd, J = 3.9, 1.0 Hz, 1 H), 7.82 (dd, J
= 5.1, 1.0 Hz, 1 H), 8.43 (s, 1 H) ppm. 13C NMR (100.61 MHz,
CDCl3): δ = 113.66 (=C-Br), 116.09 (q, J = 291.5 Hz, CF3), 128.00
(C-4), 135.47 (C-5), 137.40 (C-2), 139.07 (C-3), 140.46 (q, J =
3.3 Hz, CH=), 175.10 (q, J = 35.8, 3J = 5.2 Hz, C=O) ppm. 19F
NMR (376.5 MHz, CDCl3): δ = –68.43 ppm. MS (EI): m/z (%) =
286 (97) [M + 1]+, 284 (97) [M – 1]+, 215, 217 (100), 187, 189 (30),
108 (100), 69 (92). C8H4BrF3OS (285.08): calcd. C 33.71, H 1.41,
Br 28.03, F 19.99; found C 33.90, H 1.55, Br 29.14, F 19.98.
˜
1H NMR (400.16 MHz, CD3CN): δ = 0.85 (t, J = 7.3 Hz, 6 H),
1.45–1.60 (m, 4 H), 2.90–3.05 (m, 2 H), 3.45–3.55 (m, 2 H), 3.73
(s, 3 H), 3.77 (s, 3 H), 4.69 (br. s, 1 H), 5.33 (s, 1 H), 6.50 (d, J =
8.9 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H) ppm. 1 3 C NMR
(100.61 MHz, CD3CN): δ = 11.66 (CH3), 21.10 (CH2), 53.29
(NCH2), 56.34, 56.66 (OCH3), 86.21 (q, J = 30.0 Hz, C-OH), 99.35
(CH=), 107.17, 115.34, 122.57 (CH aryl), 124.71 (q, J = 289 Hz,
CF3), 135.71, 146.21, 151.30 (C aryl), 153.44 (=C-N) ppm. 19F
NMR (376.5 MHz, CDCl3): δ = –77.97 ppm. MS (EI): m/z (%) =
359 (81) [M]+, 330 (100), 270 (28), 248 (29), 218 (17). C18H24F3NO3
(359.39): calcd. C 60.16, H 6.73, N 3.90; found C 60.26, H 7.21, N
4.01.
General Procedure for the Reaction of Ketones 3a–d with Amines: A
mixture of bromoketone 3a–d and secondary amine (2 equiv.) in
ether or THF was stirred at room temperature overnight. The sol-
vent was removed, and the analytically pure samples of indenoles
4a,d–f, aminoenones 5a,b, or indanone 8 were obtained by further
column chromatography (silica gel, ether/hexane).
2-(Dibutylamino)-4,7-dimethoxy-1-(trifluoromethyl)-1H-inden-1-ol
(4f): Yield 36%. Solid, m.p. 56–57 °C. IR (KBr): ν = 1680 (C=C),
˜
1
3510 (OH) cm–1. H NMR (400.16 MHz, CDCl3): δ = 0.93 (t, J =
The following compounds were obtained by this procedure.
7.5 Hz, 6 H), 1.27–1.40 (m, 4 H), 1.50–1.65 (m, 4 H), 2.95–3.10 (m,
2-(Diethylamino)-1-(trifluoromethyl)-1H-inden-1-ol (4a): Yield 55%. 2 H), 3.50–3.65 (m, 2 H), 3.80 (s, 3 H), 3.83 (s, 3 H), 4.42 (br. s, 1
Oil. IR (KBr): ν = 1698 (C=C), 3510 (OH) cm–1. 1H NMR H), 5.40 (s, 1 H), 6.44 (d, J = 8.9 Hz, 1 H), 6.74 (d, J = 8.9 Hz, 1
˜
(400.16 MHz, CDCl3): δ = 1.14 (t, J = 7.0 Hz, 6 H), 3.20–3.35 (m,
2 H), 3.45–3.60 (m, 2 H), 5.38 (s, 1 H), 5.55 (br. s, 1 H), 6.85–6.95
H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 14.11 (CH3), 20.38,
29.50 (CH2), 50.92 (NCH2), 55.88, 56.28 (OCH3), 85.53 (q, J =
(m, 2 H), 7.15–7.35 (m, 2 H) ppm. 13C NMR (100.61 MHz, 30.0 Hz, C-OH), 98.93 (CH=), 105.80, 114.15, 122.20 (CH, aryl),
Eur. J. Org. Chem. 2007, 6039–6045
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6043

A. Yu. Rulev et al.
68% yield. IR (KBr): ν = 1767 (C=O), 3405 (O-H) cm–1. 1H NMR
FULL PAPER
125.39 (q, J = 289 Hz, CF3), 132.22, 145.56, 150.17 (C aryl), 152.40
˜
(=C-N) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –77.99 ppm. MS (400.16 MHz, CDCl3): δ = 3.46 (A part of AB system, J = 21.5 Hz,
(EI): m/z (%) = 387 (100) [M]+, 344 (58), 302 (65), 270 (18), 218 1 H), 3.72 (B part of AB system, J = 21.5 Hz, 1 H), 3.80 (s, 3 H),
(15). C20H28F3NO3 (387.45): calcd. C 62.00, H 7.28, N 3.62; found
C 61.80, H 7.31, N 3.55.
6.96 (d, J = 8.3 Hz, 1 H), 7.05 (s, 1 H), 7.21 (d, J = 8.3 Hz, 1
H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 40.85 (CH2), 55.63
(CH3O), 79.47 (q, J = 30 Hz, C-OH), 110.42 (C-7), 119.01 (C-5),
123.33 (q, J = 286 Hz, CF3), 126.15 (C-4), 129.07 (C-9), 135.76 (C-
8), 160.07 (C-OMe), 207.80 (C=O) ppm. 19F NMR (376.5 MHz,
CDCl3): δ = –78.55 ppm. MS (EI): m/z (%) = 246 (40) [M]+, 218
(63), 149 (100), 121 (48). C11H9F3O3 (246.19): calcd. C 53.67, H
3.68; found C 53.64, H 3.72.
3-(Dipropylamino)-1,1,1-trifluoro-4-(2-thienyl)-3-buten-2-one (5a):
1
Yield 20%. Oil. IR (KBr): ν = 1595 (C=C), 1682 (C=O) cm–1. H
˜
NMR (400.16 MHz, CDCl3): δ = 0.83 (t, J = 7.5 Hz, 6 H), 1.45–
1.55 (m, 4 H), 2.90–3.05 (m, 4 H), 7.11 (dd, J = 5.2, 3.8 Hz, 1 H),
7.45 (d, J = 3.8 Hz, 1 H), 7.59 (d, J = 5.2 Hz, 1 H), 7.74 (s, 1 H)
ppm. 13C NMR (100.61 MHz, CDCl3): δ = 12.08 (CH3), 21.27
(CH2), 55.41 (NCH2), 116.72 (q, J = 293 Hz, CF3), 126.92 (C-4),
134.44 (C-5), 135.43 (C-3), 136.60 (=C-N), 136.80 (C-2), 138.76 (q,
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of compounds 3a,c,d, 4e,f, 5a, and
3
J = 4 Hz, CH=), 179.39 (q, J = 32.5, J = 3.7 Hz, C=O) ppm. 19F
8 and 2D NMR for ketone 3c and indenol 4e.
NMR (376.5 MHz, CDCl3): δ = –69.99 ppm. MS (EI): m/z (%) =
305 (83) [M]+, 276 (100), 179 (22), 123 (27). C14H18F3NOS
(305.36): calcd. C 55.07, H 5.94, N 4.59; found C 55.29, H 6.01, N
4.39.
Acknowledgments
We thank Mr. Yu. A. Chuvachev for his technical assistance with
mass spectrometry.
3-(Dibutylamino)-1,1,1-trifluoro-4-(2-thienyl)-3-buten-2-one (5b):
1
Yield 23%. Oil. IR (KBr): ν = 1590 (C=C), 1683 (C=O) cm–1. H
˜
NMR (400.16 MHz, CDCl3): δ = 0.83 (t, J = 7.0 Hz, 6 H), 1.15–
1.25 (m, 4 H), 1.35–1.45 (m, 4 H), 2.90–2.98 (m, 4 H), 7.09 (dd, J
= 5.1, 3.9 Hz, 1 H), 7.42 (d, J = 3.9 Hz, 1 H), 7.56 (d, J = 5.1 Hz,
1 H), 7.71 (s, 1 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ =
14.15 (CH3), 20.95, 30.16 (CH2), 53.28 (NCH2), 116.77 (q, J =
293 Hz, CF3), 126.91 (C-4), 134.41 (C-5), 135.35 (C-3), 136.82 (=C-
N), 136.93 (C-2), 138.63 (q, J = 4.0 Hz, CH=), 179.46 (q, J = 33.0,
3J = 3.7 Hz, C=O) ppm. 19F NMR (376.5 MHz, CDCl3): δ =
–70.00 ppm. MS (EI): m/z (%) = 333 (57) [M]+, 290 (100).
C16H22F3NOS (333.42): calcd. C 57.64, H 6.65, N 4.20, S 9.62;
found C 57.19, H 6.40, N 4.14, S 9.16.
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3-(Dibutylamino)-1,1,1-trifluoro-4-(4-methoxyphenyl)-3-buten-2-one
(6a): 1H NMR (400.16 MHz, CDCl3): δ = 0.93 (t, J = 7.0 Hz, 6
H), 1.25–1.35 (m, 4 H), 1.45–1.55 (m, 4 H), 2.90–2.98 (m, 4 H),
3.74 (s, 3 H), 5.89 (s, 1 H), 6.70–6.80 (m, 2 H), 6.90–7.05 (m, 2 H)
ppm. 13C NMR (100.61 MHz, CDCl3): δ = 13.85 (CH3), 20.30,
28.50 (CH2), 50.30 (NCH2), 55.10 (CH3O), 114.30 (C-3,5), 115.00
(q, J = 294 Hz, CF3), 115.80 (CH=), 129.00 (C-2,6), 141.10 (C-1),
158.50 (=C-N), 158.8 (Car-O), 186.90 (qd, J = 10.3, 34.5 Hz, C=O)
ppm. 19F NMR (376.5 MHz, CDCl3): δ = –75.00 ppm. 15N NMR
(40.55 MHz, CDCl3): δ = –314.00 (3JH–N = 1.5 Hz) ppm.
[6] a) A. Yu. Rulev, N. A. Keiko, M. G. Voronkov, Russ. Chem.
Bull. 1996, 105, 125–128, b) A. Yu. Rulev, J. Maddaluno, Eur.
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4-(2,5-Dimethoxyphenyl)-3-(dipropylamino)-1,1,1-trifluoro-3-buten-
2-one (6b): 1H NMR (400.16 MHz, CDCl3): δ = 0.87 (t, J = 7.2 Hz,
6 H), 150–1.60 (m, 4 H), 2.85–2.95 (m, 4 H), 3.70 (s, 6 H), 5.87 (s, 1
H), 6.70–6.80 (m, 2 H), 6.68 (s, 1 H) ppm. 13C NMR (100.61 MHz,
CDCl3): δ = 11.75 (CH3), 20.25 (CH2), 53.48 (NCH2), 56.25, 56.86
(OCH3), 112.56, 113.66, 113.81 (CH aryl), 120.86 (C aryl), 125.30
(q, J = 282.0 Hz, CF3), 116.40 (CH=), 144.10 (=C-N), 150.95,
154.69 (Car-O), 186.56 (q, J = 34.4 Hz, C=O) ppm. 19F NMR
(376.5 MHz, CDCl3): δ = –74.67 ppm.
[7] A. Yu. Rulev, S. V. Fedorov, Yu. A. Chuvashev, M. G. Voron-
kov, Zh. Org. Khim. 2003, 39, 691–694 (in Russian).
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N. A. Keiko, M. G. Voronkov, Magn. Reson. Chem. 1997, 533–
537 and references cited therein.
1-Hydroxy-6-methoxy-1-(trifluoromethyl)-1,3-dihydro-2H-indan-2-
one (8): A mixture of bromoketone 3b (386 mg, 1.25 mmol) and
dibutylamine (330 mg, 2.5 mmol) in diethyl ether (10 mL) was
stirred at room temperature for 24 h. The solvent was removed,
and water (0.2 mL) and two drops of HCl (conc.) were added to
the residue. After 2 h stirring, ether (10 mL) was added. The or-
ganic layer was separated, and the aqueous layer was extracted with
diethyl ether (3ϫ10 mL). The combined organic layer was dried
with MgSO4. The solvent was removed, and the residue was puri-
fied by column chromatography (silica gel, ether/hexane, 2:1) to
give 8 (145 mg, 47%) as white solid. M.p. 153–154 °C. The same
reaction with diethylamine as nucleophile afforded indanone 8 in
6044
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6039–6045

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2094.
Received: July 3, 2007
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Published Online: October 19, 2007
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6045