One-pot synthesis of functionalized indenols from 2-bromoalkenyl trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tet.2008.06.069

An elegant one-pot synthesis of indenols was successfully realized starting from 3-aryl-2-bromopropenyl trifluoromethyl ketones and secondary amines. The synthesis proceeds through domino reactions including captodative aminoenones as a key intermediate.

Full text of DOI:10.1016/j.tet.2008.06.069

Tetrahedron 64 (2008) 8073–8077
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Tetrahedron
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One-pot synthesis of functionalized indenols from 2-bromoalkenyl
trifluoromethyl ketones
,
a
b
Alexander Yu. Rulev a , Igor A. Ushakov , Valentin G. Nenajdenko
*
a A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky Street, Irkutsk 664033, Russia
b Department of Chemistry, Moscow State University, 119899 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 April 2008
Received in revised form 29 May 2008
Accepted 19 June 2008
Available online 24 June 2008
An elegant one-pot synthesis of indenols was successfully realized starting from 3-aryl-2-bromopropenyl
trifluoromethyl ketones and secondary amines. The synthesis proceeds through domino reactions in-
cluding captodative aminoenones as a key intermediate. When bromoenones having a donor substituent
in meta-position of the aromatic ring were subjected to this reaction, the mixture of two isomeric in-
denols was formed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Indenols
Enones
Domino reactions
1. Introduction
trifluoromethyl ketones (1) and secondary amines.6 As a continua-
tion of these studies we have now examined the dependence of the
Small bicyclic molecules are frequently found in nature and are
attracting increased attention from organic and pharmaceutical
chemists.1 Among these compounds, indenols have a particular
value due to both their broad spectrum of biological activity and
their wide-ranging utility as synthetic tools in the design of various
bioactive molecules.2 In light of this interest in the indene skeleton,
much attention has been done in the development of their efficient
synthesis. The most typical reported methods toward the synthesis
of indenol derivatives include different transition metal catalyzed
carbocyclizations,2a,b a modified Vilsmeier reaction,2a and oxida-
tion of preformed indan structures.3 Recently, the first example of
the preparation of 1-indenols through acid mediated intra-
molecular electrophilic aromatic substitution process has been
reported.4
above reaction on the structure of the initial bromoenones. In this
paper, the reaction features and the extension of this methodology
to enones containing a substituent in the meta-position of the
aromatic ring are discussed.
2. Results and discussion
Trifluoromethyl(alkenyl)ketones 1 are now readily available
building blocks and widely used for the construction of different
carbo- and heterocycles.7 The synthesis of their halogen-bearing
derivatives 3a–d was carried out in high yield by a bromination–
dehydrobromination sequence without isolation of the in-
termediate dibromoderivatives 2a–d as described previously
(Scheme 1).6
At the same time the intensive development of organofluorine
chemistry over the last decades is well documented.5 Reasons for
the popularity of such compounds is the dramatic effects on the
chemical, physical, and biological properties of the parent com-
pound caused by the introduction of a fluorine-containing group
into the molecule. In this respect, the fluorinated functionalized
indenols are of great interest from both synthetic and biological
points of view. Very recently we have developed a synthesis of
1-trifluoromethyl-2-aminoindenols (3) from 2-bromoalkenyl
According to NMR spectroscopic data, the bromoenones 3a–
d exist as a single geometric isomer. Since these compounds have
only one olefinic proton, the determination of their configuration is
a non-trivial task. The (Z)-configuration of para-substituted enones
3c,d was assigned on the basis of the concerted application of
1H–1H 2D homonuclear experiment NOESY and 1H–13C 2D hetero-
nuclear experiment HMBC, as well as 13C NMR spectra without
proton decoupling (Fig. 1). For example, in the spectrum of enone
3c there is one NOE peak between the resonance of the olefinic
proton and the ortho-protons of the aromatic ring. The value of the
3
vicinal coupling constant JC–H between the proton of the H–C]
group and the carbonyl carbon atom in enone 3c is 5.2 Hz. It
is known, that this constant lies between 0 and 6 Hz for the
* Corresponding author. Fax: þ7 3952 419346.
E-mail address: rulev@irioch.irk.ru (A.Yu. Rulev).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.069

8074
A.Yu. Rulev et al. / Tetrahedron 64 (2008) 8073–8077
Br
O
O
O
i
ii
CF3
CF3
CF3
X
X
X
Br
2a-d
Br
1a-d
3a-d
X = m-Me (a) (81%)
m-MeO (b) (88%)
p-Me (c) (89%)
p-MeO (d) (86%)
Scheme 1. Reagents and conditions: (i) Br2, 10 ꢁC, CHCl3; (ii) Et3N, 10 ꢁC, Et2O.
s-cis-isomer and 9–14 Hz for the s-trans-one.8 The additional con-
firmation of this assignment has been obtained by the analysis of
their IR spectra: the ratio of integrated intensities observed for the
C]O and C]C stretching bands strongly suggests a s-cis-confor-
mation of the C]C–C]O moiety.9 Enones 3a,b bearing a sub-
stituent in meta-position of the aromatic ring have cross-peaks
with both H-2 and H-6 aromatic protons in the NOE spectra. Their
configuration was determined by measuring the coupling constant
between the olefinic proton and the carbonyl carbon atom: for both
conditions (rt, ether as a solvent, without catalyst) (Scheme 2). In
these cases, the intermediate aminoenones 4c,d can be detected by
NMR spectroscopy. Thus, when bromoenones 3c,d were treated
with dipropyl- or dibutylamine, a mixture of the corresponding
aminoenones 4c,d and indenols 5a,b was formed in a certain period
of time. In each case, the 1H NMR spectra exhibit two singlets of the
olefinic proton of the aminoenones
(dCH] 6.01 ppm for 4c,
NR2¼NPr2 and 5.89 ppm for 4d, NR2¼NBu2) and the indenols (dCH]
5.38 and 5.25 ppm for 5a,b, respectively). The molar ratio 4d/5b
was 10:1 after 15 h of reaction, the ratio 4c:5a was 2.5:1 after
a period of 20 h at rt.
3
enones the values of JC–H (ca. 5.7 Hz) correspond to W disposed
H–C] and C]O groups.
It would be interesting to see whether aminoenone 4 is a pre-
cursor of the indenol 5. To establish a sequence of transformations,
we have monitored the reaction of bromoenone 3d with dibutyl-
amine. At first, in the 1H NMR spectrum there are two singlets in
the field of the olefinic protons. As the reaction progresses, the
intensity of the downfield peak decreases, while the intensity of
highfield one increases. The analogous changes are observed in the
13C NMR spectra. For example, the quartet of the carbonyl carbon
atom of enone 4d (NR2¼NBu2) (186.90 ppm) disappears and the
signal of quaternary carbon atom C(OH)CF3 of indenol 5b
(83.00 ppm) appears simultaneously. These facts indicate clearly
that captodative aminoenones 4 are really direct precursor of the
indenols 5.
CF3
Br
H
H
H
H
O
H
H
H
H
H
O
O
H
X
X
H
X
H
CF3
CF3
H
Br
Br
H
H
3c,d
3a,b
NOESY
HMBC
Figure 1. Main NOESY and HMBC correlations for bromoenones 3a–d.
The IR spectra of bromoenones 3a,b exhibit a carbonyl band at
1705–1707 cmꢀ1 and a more intensive band at 1585–1594 cmꢀ1
attributed to nC]C. For this reason a s-cis-conformation of these
molecules was deduced.
We found that the treatment of p-substituted 4-aryl-3-bromo-
1,1,1-trifluorobut-3-en-2-ones 3c,d with secondary amines
(2 equiv) affords the target indenols in good yield under mild
We next tested the hypothesis that the structure of the target
indenol depends on the position of the substituent in the aromatic
ring of the initial bromoenone. Indeed, as with enones 3c,d, their
analogs 3a,b, having a meta-substituted aromatic ring containing
an electron-donating group such as methyl- or methoxy, might
lead at the first step to captodative aminoenones 4a,b, which can
undergo intramolecular electrophilic aromatic substitution on
O
CF3
+ HNR2
X
Br
3a-d
X
NR2
OH
F3C
NR2
CF3
for 4c,d
6a-c
NR2
OH
X
for 4a,b
X
O
F3C
X
HO
4a-d
CF3
NR2
5a,b
7a-c
3,4: X = m-Me (a)
6,7 : X = Me, NR2 = NEt2 (a)
X = Me, NR2 = NPr2 (b)
X = MeO, NR2= NEt2 (c)
5: X = Me, NR2 = NPr2 (a)
X = MeO, NR2 = NBu2 (b)
m-MeO (b)
p-Me (c)
p-MeO (d)
Scheme 2. Conditions: Et2O, rt.

A.Yu. Rulev et al. / Tetrahedron 64 (2008) 8073–8077
8075
both ortho-carbons. But in this case, the attack at positions 2 and 6
COCF3
H
COCF3
H
results in different indenol derivatives. In fact, when the reaction of
secondary amines was performed with meta-substituted bromo-
enones 3a,b, a mixture of two isomeric indenols 6 and 7 was al-
ways formed. The 1H NMR spectra of the reaction mixtures exhibit
two singlets at 5.20–5.30 ppm arising from the olefinic proton of
the indenols. No low-field signals of the proton of the CH] group
of their precursors were detected in these cases. Therefore, ami-
noenones 4a,b become more active in the last step of the reaction
then their para-substituted isomers 4c,d. These results are not
surprising and can be interpreted in terms of aromatic electrophilic
substitution, since methyl- and methoxy groups are ortho, para
directors and show activating effects in positions 2 and 6 of the
aromatic ring. The reaction is quite regioselective: the ratio of
isomeric indenols 6a,b:7a,b is ~10:1, and in the cases of 6c:7c
achieves ~20:1. The preferable formation of indenol 6 is likely to be
due to the steric hindrance by the meta-substituent.
R2N
Br
HNR2
R2N
H
SN
H
NR2
Ar
Ar
- HNR2
Ar
E
R2NH
Ad
O
COCF3
NR2
4a-d
CF3
Ar
Br
3a-d
Scheme 4. Ad–SN–E sequence of nucleophilic vinylic substitution.
3. Conclusion
We have shown that bromoalkenyl trifluoromethyl ketones are
suitable starting materials for one-pot conversion into functionally
substituted 1-indenols. It is surprising that this reaction occurs in
the very mild conditions without catalyst. This fact can be
explained by the presence of a strong electron-withdrawing group
CF3. The presence of the enamine moiety in the indenols obtained
reveals the possibility of their transformation into the corre-
sponding indanones.
The enamine moiety in indenols is easily hydrolyzed to give
the corresponding carbonyl derivatives. The accompanying hy-
drolysis reaction begins during silica gel column chromatogra-
phy. That is why some of the sample of the indenols 5–7 could
not be chromatographed quantitatively. For this reason, the yield
of the purified target compounds decreased, and some of the
indenol and the respective indanone were isolated simulta-
neously. For instance, when the crude mixture obtained after the
treatment of enone 3c with dipropylamine was purified, the
mixture of isomeric indenols (6b and 7b) and indanone 8 was
isolated in 46 and 23% yields, respectively. The same final
product 8 was isolated in the yield of 35% when the indenol 6a
was treated with water in CH2Cl2 in the presence of HCl for
a day at rt (Scheme 3).
4. Experimental
4.1. General remarks
1H, 13C, and 19F NMR spectra were recorded on a Bruker AVANCE
400 MHz spectrometer at 400.16, 100.61, and 376.5 MHz, re-
spectively, for solution in CDCl3. Chemical shifts (d) in parts per
million are reported using residual chloroform (7.25 for 1H and
77.20 for 13C) as internal reference. The coupling constants (J) are
given in hertz. The concerted application of 1H–1H 2D homonuclear
experiments COSY11 and NOESY12 as well as 1H–13C 2D hetero-
nuclear experiments HSQC13 and HMBC14 was used for the dis-
tinction 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 on a Hewlett–Packard HP 5971A in-
strument (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 solvents were dried
according to standard procedures and freshly distilled prior to use.
Trifluoromethyl(alkenyl)ketones 1a–d were prepared as reported
previously.15 The synthesis of bromoenone 3d and the indenol 5b
was described in our previous paper.6
NR2
OH
O
OH
F3C
F3C
6a,b
8
NR2 = NEt2, NPr2
Scheme 3. Reagents and conditions: H2O/HCl/CH2Cl2, rt.
The results obtained clearly indicate that the transformation of
captodative bromoenones 3 to indenols under the treatment of
secondary amines is a multi-step process. From a mechanistic
point of view, the key steps of this reaction seem to be: (i) aza-
Michael addition of the nucleophile to the conjugated system
C]C–C]O; (ii) substitution of the bromine atom at the new tet-
rahedral carbon center by further amine; (iii) elimination of the b-
amine to give a captodative system; and (iv) finally, intramolecular
electrophilic aromatic substitution occurs leading directly to the
target indenol.
4.2. Bromination of ketones (1a–c). General procedure
Despite the absence of detecting or isolating any of the in-
termediates, the postulated scheme AdN–SN–E–SE has been con-
firmed by the following studies. Firstly, in our previous paper, we
have reported that the principal precursor of indenols was detected
by NMR spectroscopy in some cases.6 Secondly, we have shown
that the geometry of aminoenones 4 is opposite to one of the initial
bromoenones 3. This fact can be easily explained in the terms of
nucleophilic substitution of haloalkenes bearing electron-with-
drawing group (EWG) at the gem-position, which, as well known,
proceeds through a Michael addition–substitution–elimination
domino sequence (Scheme 4).10
Bromine (0.8 g, 5 mmol) in CHCl3 (5 mL) was added dropwise
over 30 min into a stirred solution of the ketones 1a–c (5 mmol) in
CHCl3 (5 mL). During the addition the temperature was kept at
þ10 ꢁC. The mixture was then stirred at rt until the orange color did
not fade away. The solvent was evaporated and a light-yellow solid
appeared. The crude productsddibromoderivatives 2a–cdwere
found suitable for further transformation without any purification.
Triethylamine (0.5 g, 5 mmol) in anhydrous ether (10 mL) was
added dropwise over 5 min into a stirred solution of the dibromo
ketones 2a–c (5 mmol) in Et2O (10 mL) at þ10 ꢁC. The mixture was
kept at rt overnight and filtered. After the solvent was evaporated,
According to NMR spectroscopy, the intermediate
b-aryl
substituted aminoenones 4 have the (E)-configuration. It has been
this configuration of aminoenones 4, which, in all the cases, favors
their intramolecular cyclization into indenols.
the a-bromoenones 3a–c were obtained by column chromatogra-
phy (3a) (silica gel, hexane/ether 1:1) or distillation at reduced
pressure (3b,c).

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A.Yu. Rulev et al. / Tetrahedron 64 (2008) 8073–8077
4.2.1. 3-Bromo-1,1,1-trifluoro-4-(3-methylphenyl)-3-
buten-2-one (3a)
(m, 2H), 5.31 (s, 1H), 6.67 (d, J¼8.0 Hz, 1H), 6.70 (d, J¼7.6 Hz, 1H),
7.06 (dd, J¼7.6, 8.0 Hz, 1H); dC (100.6 MHz, CDCl3) major isomer 6a:
12.39 (CH3CH2), 21.86 (CH3), 44.21 (NCH2), 83.08 (q, J¼30.3 Hz, C–
OH), 103.71 (CH]), 118.96 (C-4), 122.70 (C-6), 122.79 (C-7), 124.94
(q, J¼285.3 Hz, CF3), 134.61 (C-8), 140.41 (C-5), 145.19 (C-9), 152.89
(]C–N); minor isomer 7a: 12.52 (CH3CH2), 21.86 (CH3), 44.32
(NCH2), 85.30 (q, J¼30 Hz, C–OH), 103.71 (CH]), 115.68 (C-4),
125.51 (q, J¼286 Hz, CF3), 125.75 (C-6), 130.31 (C-5), 134.85 (C-7),
135.44 (C-8), 145.65 (C-9), 152.54 (]C–N); dF (376.5 MHz, CDCl3)
major isomer 6a: ꢀ78.27; minor isomer 7a: ꢀ75.47; m/z (EI) 285
(Mþ, 96), 270 (100%).
Yield 81%; white solid, mp 29 ꢁC; [Found: C, 44.97; H, 2.78; Br,
27.14; F, 19.16. C11H8BrF3O requires: C, 45.08; H, 2.75; Br, 27.26; F,
19.45%.] nmax (KBr) 1585 (C]C), 1707 (C]O) cmꢀ1
; dH (400 MHz,
CDCl3)2.50(s,3H),7.30–7.50(m, 2H), 7.79(s,1H), 7.87(d, J¼7.5 Hz,1H)
8.22 (s, 1H); dC (100.6 MHz, CDCl3) 21.39 (CH3), 116.04 (q, J¼291.4 Hz,
CF3),116.49 (]C–Br),128.57 (C-60),128.76 (C-50),132.25 (C-20),132.95
(C-30),133.07(C-40),138.63(C-10),147.47(q, J¼3.8 Hz, CH]),175.71 (q,
J¼35.3 Hz, C]O); dF (376.5 MHz, CDCl3) ꢀ68.51; m/z (EI) 294 (Mþþ1,
26), 292 (Mþꢀ1, 26), 279, 277 (37), 225, 223 (20), 116 (100%).
4.2.2. 3-Bromo-1,1,1-trifluoro-4-(3-methoxyphenyl)-3-
buten-2-one (3b)
4.3.3. 2-(Dipropylamino)-5-methyl- (6b) and 2-(dipropylamino)-
7-methyl-1-(trifluoromethyl)-1H-inden-1-ol (7b)
Yield 88%; yellow liquid, bp 95–96 ꢁC/1 mmHg; [Found: C,
42.62; H, 2.59; Br, 25.57; F, 18.78. C11H8BrF3O2 requires: C, 42.75; H,
2.61; Br, 25.85; F, 18.44%.] nmax (liquid film) 1594 (C]C), 1707
Yield 46%; oil; [Found: C, 65.11; H, 6.74; N, 4.21. C17H22F3NO
requires: C, 65.16; H, 7.08; N, 4.47%.] dH (400 MHz, CDCl3) major
isomer 6b: 0.95 (t, J¼7.3 Hz, 6H), 1.55–1.70 (m, 4H), 2.32 (s, 3H),
2.95–3.10 (m, 2H), 3.40–3.55 (m, 2H), 5.28 (s, 1H), 6.70 (d, J¼7.6 Hz,
1H), 6.71 (s, 1H), 7.16 (d, J¼7.6 Hz, 1H); minor isomer 7b: 0.95 (t,
J¼7.5 Hz, 6H), 1.55–1.70 (m, 4H), 2.47 (s, 3H), 2.95–3.10 (m, 2H),
3.40–3.55 (m, 2H), 5.30 (s, 1H), 6.67 (d, J¼8.0 Hz, 1H), 6.70 (d,
J¼7.6 Hz, 1H), 7.06 (dd, J¼7.6, 8.0 Hz, 1H); dC (100.6 MHz, CDCl3)
major isomer 6b: 11.62 (CH3CH2), 20.55 (CH2), 21.92 (CH3), 52.63
(NCH2), 83.13 (q, J¼30.3 Hz, C–OH), 103.78 (CH]), 119.10 (C-4),
122.58 (C-6), 122.79 (C-7), 124.98 (q, J¼285.3 Hz, CF3), 134.40 (C-8),
140.67 (C-5), 145.24 (C-9), 153.15 (]C–N); minor isomer 7b: 11.55
(CH3CH2), 18.28 (CH3), 52.54 (NCH2), 85.30 (q, J¼30 Hz, C–OH),
103.24 (CH]), 115.46 (C-4), 125.49 (C-6), 125.54 (q, J¼286 Hz, CF3),
130.11 (C-5), 133.43 (C-8), 134.67 (C-7), 145.50 (C-9), 152.75 (]C–
N); dF (376.5 MHz, CDCl3) major isomer 6b: ꢀ78.29; minor isomer
7b: ꢀ75.50; m/z (EI) 313 (Mþ, 64), 284 (100), 224 (44%).
(C]O) cmꢀ1
;
dH (400 MHz, CDCl3) 3.87 (s, 3H), 7.09 (d, J¼9.0 Hz,
1H), 7.41 (dd, J¼9.0, 8.8 Hz, 1H), 7.49 (d, J¼8.8 Hz, 1H), 7.58 (s, 1H),
8.18 (s, 1H); dC (100.6 MHz, CDCl3) 55.55 (OCH3), 115.93 (q,
J¼292.0 Hz, CF3), 115.96 (C-20), 116.92 (]C–Br),118.32 (C-40), 124.39
(C-60), 129.91 (C-50), 134.09 (C-10), 147.43 (q, J¼3.7 Hz, CH]), 159.72
(C-30), 175.69 (q, J¼35.5, 5.7 Hz, C]O); m/z (EI) 310 (Mþþ1, 56), 308
(Mþꢀ1, 56), 279 (MþꢀMeOþ1, 33), 277 (MþꢀMeOꢀ1, 33), 241, 239
(40), 132 (100%).
4.2.3. 3-Bromo-1,1,1-trifluoro-4-(4-methylphenyl)-3-
buten-2-one (3c)
Yield 89%; yellow liquid, bp 77 ꢁC/1 mmHg; [Found: C, 44.82; H,
2.81; Br, 27.66; F, 19.48. C11H8BrF3O requires: C, 45.08; H, 2.75; Br,
27.26; F,19.45%.] nmax (liquid film) 1585 (C]C),1705 (C]O) cmꢀ1
; dH
(400 MHz, CDCl3) 2.41 (s, 3H), 7.26 (d, J¼8.0 Hz, 2H), 7.87 (d,
J¼8.0 Hz, 2H), 8.13 (s, 1H); dC (100.6 MHz, CDCl3) 21.85 (CH3), 115.71
(]C–Br), 116.08 (q, J¼290.1 Hz, CF3), 129.70 (C-30,50), 130.28 (C-10),
131.86 (C-20,60), 143.32 (C-40), 147.24 (q, J¼3.1 Hz, CH]), 175.67 (q,
J¼35.0, 5.3 Hz, C]O); dF (376.5 MHz, CDCl3) ꢀ68.42; m/z (EI) 294
(Mþþ1, 37), 292 (Mþꢀ1, 37), 279, 277 (65), 225, 223 (44),116 (100%).
4.3.4. 2-(Diethylamino)-5-methoxy- (6c) and 2-(diethylamino)-7-
methoxy-1-(trifluoromethyl)-1H-inden-1-ol (7c)
Yield 48%; oil; [Found: C, 59.77; H, 6.04; N, 4.73. C15H18F3NO2
requires: C, 59.79; H, 6.02; N, 4.65%.] nmax (liquid film) 1168 (COC),
1592 (C]C), 3380 (OH) cmꢀ1
; dH (400 MHz, CDCl3) major isomer
6c: 1.13 (t, J¼7.5 Hz, 6H), 3.15–3.30 (m, 2H), 3.35–3.50 (m, 2H), 3.68
(s, 3H), 5.24 (s, 1H), 6.27 (dd, J¼2.0, 8.1 Hz, 1H), 6.36 (d, J¼2.0 Hz,
1H), 7.11 (d, J¼8.1 Hz, 1H); minor isomer 7c: 1.10 (t, J¼7.5 Hz, 6H),
3.15–3.30 (m, 2H), 3.35–3.50 (m, 2H), 3.79 (s, 3H), 5.23 (s, 1H), 6.29
(m, 1H), 6.35 (m, 1H), 7.00 (m, 1H); dC (100.6 MHz, CDCl3) major
isomer 6c: 12.37 (CH3CH2), 44.12 (NCH2), 55.15 (CH3O), 82.80 (q,
J¼29.9 Hz, C–OH), 102.70 (CH]), 104.70 (C-4), 106.06 (C-6), 123.92
(C-7), 125.04 (q, J¼284.9 Hz, CF3), 129.29 (C-8), 146.80 (C-9), 153.91
(]C–N), 161.97 (C-5); minor isomer 7c: 12.37 (CH3CH2), 44.30
(NCH2), 56.34 (CH3O), 84.10 (q, C–OH), 101.30 (CH]), 110.6 (C-6),
115.30 (C-4), 122.4 (C-8), 125.2 (q, CF3), 127.60 (C-5), 147.4 (C-9),
152.6 (]C–N), 155.35 (C-7); dF (376.5 MHz, CDCl3) major isomer 6c:
ꢀ76.69; minor isomer 7c: ꢀ74.10; m/z (EI) 285 (Mþ, 96), 270 (100%).
4.3. The reaction of ketones (3a–d) with secondary amines.
General procedure
A mixture of bromoenones 3a–d and secondary amine (2 equiv)
in ether was stirred at rt overnight. The solvent was removed and
analytically pure samples of indenols 4a,d–f, aminoenones 5a,b, or
indanone 8 were obtained by further column chromatography
(silica gel, ether/hexane).
The following compounds were obtained by this procedure.
4.3.1. 2-(Dipropylamino)-6-methyl-1-(trifluoromethyl)-
1H-inden-1-ol (5a)
Yield 43%; oil; [Found: C, 65.44; H, 6.65; N, 4.78. C17H22F3NO
requires: C, 65.16; H, 7.08; N, 4.47%.] nmax (liquid film) 1592 (C]C),
4.3.5. 1-Hydroxy-5-methyl-1-(trifluoromethyl)-1,3-dihydro-2H-
indan-2-one (8)
3373 (OH) cmꢀ1
;
dH (400 MHz, CDCl3) 0.96 (t, J¼7.3 Hz, 6H), 1.55–
1.70 (m, 4H), 2.36 (s, 3H), 2.95–3.10 (m, 2H), 3.37 (br s, 1H), 3.45–
3.60 (m, 2H), 5.35 (s, 1H), 6.81 (d, J¼7.4 Hz, 1H), 6.78 (d, J¼7.4 Hz,
1H), 7.16 (s, 1H); dC (100.6 MHz, CDCl3) 11.65 (CH3), 20.50 (CH2),
21.32 (CH3), 52.64 (NCH2), 83.30 (q, J¼30.2 Hz, C–OH), 104.24
(CH]), 117.89 (C-4), 123.84 (C-5), 124.88 (q, J¼285 Hz, CF3), 131.17
(C-7), 131.74 (C-6), 137.54 (C-8), 142.21 (C-9), 152.23 (]C–N).
A mixture of bromoketone 3c (293 mg, 1 mmol) and diethyl-
amine (160 mg, 2.2 mmol) in ether (10 mL) was stirred at rt for 24 h.
The solvent was removed giving a mixture (285 mg) containing
mainly the target indenols 5a and 6a, which was used in the next
step without any purification. Water (0.2 mL) and two drops of HCl
(concd) were added tothe residue in CH2Cl2 (10 mL) and the mixture
was stirred for 24 h at rt. The solvent was removed, the residue was
purified by column chromatography (silica gel, ether/hexane 1:2) to
give 8 (80 mg, 35%) as a white solid, mp 79 ꢁC; [Found: C, 57.69; H,
4.03. C11H9F3O2 requires: C, 57.40; H, 3.94%.] nmax (KBr) 1760 (C]O),
4.3.2. 2-(Diethylamino)-5-methyl- (6a) and 2-(diethylamino)-7-
methyl-1-(trifluoromethyl)-1H-inden-1-ol (7a)
Oil; dH (400 MHz, CDCl3) major isomer 6a: 1.15 (t, J¼7.5 Hz, 6H),
2.30 (s, 3H), 3.20–3.30 (m, 2H), 3.45–3.55 (m, 2H), 5.30 (s, 1H), 6.69
(d, J¼7.6 Hz, 1H), 6.70 (s, 1H), 7.17 (d, J¼7.6 Hz, 1H); minor isomer
7a: 1.07 (t, J¼7.5 Hz, 6H), 2.47 (s, 3H), 3.20–3.30 (m, 2H), 3.45–3.55
3420 (O–H) cmꢀ1
; dH (400 MHz, CDCl3) 2.43 (s, 3H), 3.55 (A part of
AB-system, J¼21.6 Hz, 1H), 3.73 (s, 1H), 3.81 (B part of AB-system,
J¼21.6 Hz, 1H), 7.20 (s, 1H), 7.23 (d, J¼8.0 Hz, 1H), 7.51 (d, J¼8.0 Hz,

A.Yu. Rulev et al. / Tetrahedron 64 (2008) 8073–8077
8077
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1H); dC (100.6 MHz, CDCl3) 22.00 (CH3), 41.39 (CH2), 79.07 (q,
J¼30.6 Hz, C–OH), 123.40 (q, J¼286.4 Hz, CF3), 125.69 (C-4), 126.53
(C-7), 129.66 (C-6), 131.96 (C-9), 137.35 (C-8), 141.54 (C-5), 208.03
(C]O); m/z (EI) 230 (Mþ, 23), 161 (76), 133 (100), 105 (53%).
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Acknowledgements
We thank Mr. Yu. A. Chuvachev for his mass-spectrometry
technical assistance. This work was supported by the Russian
Foundation for Basic Research (Grant no. 08-03-00067-a).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.06.069.
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