Synthesis of functionalized m-bistrifluoromethylbenzenes via cyclocondensation of 1,1,1,5,5,5-hexafluoroacetylacetone with enamines

Article abstract of DOI:10.1016/j.tet.2005.01.075

The reaction of 1,1,1,5,5,5-hexafluoroacetylacetone with push-pull enamines having a methyl group at the α-position was investigated. It was found that the reaction is sensitive both to the structure of enamines and to reaction conditions. As a result, a set of bistrifluoromethyldialkylanilines and ethyl bistrifluoromethylsalicylate was prepared. Plausible mechanisms and factors influencing the course of the reaction are discussed.

Full text of DOI:10.1016/j.tet.2005.01.075

Tetrahedron 61 (2005) 2839–2847
Synthesis of functionalized m-bistrifluoromethylbenzenes
via cyclocondensation of 1,1,1,5,5,5-hexafluoroacetylacetone
with enamines
*
Dmitriy M. Volochnyuk, Alexander N. Kostyuk, Dmitriy A. Sibgatulin
and Alexander N. Chernega
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanskaya 5, 02094 Kyiv-94, Ukraine
Received 15 October 2004; revised 4 January 2005; accepted 20 January 2005
Abstract—The reaction of 1,1,1,5,5,5-hexafluoroacetylacetone with push–pull enamines having a methyl group at the a-position was
investigated. It was found that the reaction is sensitive both to the structure of enamines and to reaction conditions. As a result, a set of
bistrifluoromethyldialkylanilines and ethyl bistrifluoromethylsalicylate was prepared. Plausible mechanisms and factors influencing the
course of the reaction are discussed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
proved to be one of the most convenient methods for the
synthesis of bistrifluoromethylated pyrazoles, isoxazoles,8
pyridines,9 pyrimidines,10 pyrroles,11 and diazepines.12 To
the best of our knowledge, the approach has not been
applied to the synthesis of bistrifluoromethylated benzenes
yet. In our previous work we have demonstrated the
possibility of using tertiary push–pull enamines as 1,3-
CCC-bisnucleophiles in the reactions with b-trifluoro-
acetylvinyl ethers for synthesis of monotrifluoromethylated
functionalized dialkylanilines.13 In this work we report our
results on the reaction of tertiary push–pull enamines having
a methyl group at the a-position with 1,1,1,5,5,5-hexa-
fluoroacetylacetone 1.
Introduction of the trifluoromethyl group, an important
functional group in organic chemistry allows chemists to
considerably change physico-chemical properties of organic
molecules.1 Thus, derivatives of m-bistrifluoromethyl-
benzene are actively used in the design and synthesis of
various ligands2 and pharmaceutical substances.3,4 Further
development of methods for synthesis of functionalized
m-bistrifluoromethylbenzenes is investigated. Although this
fragment is actively used in many pharmaceutical research
projects, in almost all of them 3,5-trifluoromethylaniline
is used due to a known synthetic procedure described
years ago.5
2. Results and discussion
A few works such as the palladium catalyzed arylation of
amines with 1-bromo-3,5-bis(trifluoromethyl)benzene6 and
the use of 2-methoxy-4,6-bis(trifluoromethyl) phenyl-
lithium7 give alternative approaches to the synthesis of
bistrifluoromethylbenzene derivatives.
2.1. Interaction of 1,1,1,5,5,5-hexafluoroacetylacetone
with b-dialkylaminocrotonitriles
Enamines 2 derivatives of b-aminocrotonitrile react with
1,1,1,5,5,5-hexafluoroacetylacetone 1 in benzene at room
temperature for 2–3 days affording a mixture of arene
hydrate 3 and diol 4 in combined yield 35–40%, precipitated
from the reaction mixture. Analysis of the reaction mixture
by 19F NMR reveals presence of the starting b-diketone 1
and traces of benzenes 5. Numerous attempts to optimize the
reaction conditions failed. Increasing the reaction tempera-
ture or time lead to formation of benzenes 5 and pyridone 6
products of the self-condensation of enamines 2. Carrying
At the same time the commercially available symmetrical
1,3-biselectrophilic building block—1,1,1,5,5,5-hexafluoro-
acetylacetone has been used for synthesis of bistrifluoro-
methylated heterocyclic compounds. This approach has
Keywords: 1,1,1,5,5,5-Hexafluoroacetylacetone; Push–pull enamines; Tri-
fluoromethylated benzenes; Cyclocondensation.
* Corresponding author. Tel.: C380 44 5373218; fax: C380 44 5373253;
e-mail: a.kostyuk@enamine.net
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.075

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D. M. Volochnyuk et al. / Tetrahedron 61 (2005) 2839–2847
Scheme 2.
Scheme 1. Reagents and conditions: (i) benzene, rt, 2–3 days; (ii) benzene,
reflux, 2 h; (iii) acetone, rt, 7–10 days; (iv) toluene, PTSA, reflux, 30 min.
out the reaction in boiling benzene or methanol results in
conversion of 60–70% of the starting enamine, but the ratio
of cyclization product 4 to pyridone 6 is ca. w7:1 for
enamine 2a, and w4:6 for enamine 2c (Scheme 1). The ratio
of reaction products 3 and 4 depends on the structure of the
dialkylamino residue and reaction conditions (Table 1).
Thus, for pyrrolidine enamine 2a, the diol was registered in
trace amount, while in the case of morpholine enamine 2c,
the ratio of diol/‘hydrate’ was 1:1. At the same time for
enamine 2c, diol 4c was not registered at all when the
reaction was run at 40–50 8C. It is worth noting that under
the conditions in which hydrates 3 are transformed into
benzenes 5, diol 4 remains intact. Thus, we can draw the
conclusion that diols 4 are not intermediate products in the
chain of transformations 2/3/5. We suppose that
formation of 3 and 4 proceeds by different mechanisms. In
the case of 3, hexafluoroacetylacetone 1 reacts as an enol
affording dienamine 7, followed by 6-exo-trig cyclization to
give ‘hydrate’ 3 (Scheme 2). At the same time the key step
in the formation of diol 4 is the ene-reaction of enamines 2
with hexafluoroacetylacetone 1 which react in the ketone
form like MeTFP,14 affording terminal enamines 9 followed
by spontaneous cyclization into diol 4. Formation of only
one possible diastereomer of 4 whose stereochemistry was
solved by the single X-ray diffraction study could be
rationalized by intramolecular hydrogen bonding (Scheme
3). Indirect proof for the proposed mechanisms is the growth
of the ‘hydrate’ 3 produced upon increase of C-nucleo-
philicity of the enamines. Higher nucleophilicity would
facilitate the reaction presented on Scheme 2,13 and would
not influence the reaction given on Scheme 3.14
Scheme 3.
The structures of compounds synthesized were confirmed
by a set of physico-chemical methods, and for compounds
3a and 4c single X-ray diffraction studies were accom-
plished. (Figs. 1 and 2). It is worth noting that compounds of
type 3 are allied to so-called arene hydrates whose simple
representatives are highly unstable compounds under
normal conditions.15 In our previous work13 two types of
arene hydrates (type A and B, Fig. 3) which are stable under
normal conditions have been described. In our viewpoint
their stability is stipulated both by kinetic and thermo-
dynamic factors. Substances 3 like arene hydrates of type A
and B are stable compounds in the solid state, melting
without decomposition. On heating in solution in the
presence of catalytic amounts of acids such as PTSA
‘arene hydrates’ 3 eliminate water irreversibly turning into
the corresponding benzenes 4. It should be noted that arene
Table 1. Yields of products of the reaction of enamines 2 with hexafluoroacetylacetone 1
Enamine
Conditions
Yield (%)
3
4
5
6
2aa
2ba
2ca
2ca
2ab
2cb
C6H6, rt, 3 days
C6H6, rt, 3 days
C6H6, rt, 3 days
C6H6, 40 8C, 3 h
C6H6, reflux, 4 h
C6H6, reflux, 4 h
31
26
21
14
—
—
Traces
9
23
Traces
—
—
6
3
5
15
43
28
—
—
—
—
6
24
a Refer according to 19F NMR spectra of reaction mixture.
b Yields of 5 refer according to 19F NMR spectra of reaction mixture and yield of 6 is for isolated product.

D. M. Volochnyuk et al. / Tetrahedron 61 (2005) 2839–2847
2841
hydrates 3 hold an intermediate position in a stability series
with respect to acidic catalysed elimination of water
between previously described arene hydrates of types A
and B. We suppose that unlike arene hydrates of types A and
B the stability of 3 is stipulated only by kinetic factors,
namely by strong destabilization of the forming carbcation
on E1-elemination of water with two concurrently influen-
cing trifluoromethyl groups. Besides, there are some similar
stable arene hydrates of type C described in the literature
where the ester group acts as an acceptor instead of the
trifluromethyl group.16
2.2. Interaction of 1,1,1,5,5,5-hexafluoroacetylacetone
with b-dialkylaminocrotonoesters and a-methyl-b-
enaminones
Figure 1. A perspective view and labeling scheme for the molecule 4a.
In going from enaminonitriles 2 to esters of b-dialkyl-
aminocrotonic acids 11, the reaction of the latter with
hexafluoroacetylacetone 1 is complicated with side reac-
tions. Besides the targeted dialkylaminoanthranilic acid
esters 12, symmetrical dialkylanilines 13, and salicylic acid
ester 14 formed in the reaction (Scheme 4). Increase of the
basicity of dialkylamino residue leads to higher content of
by-products (Table 2). We supposed that the cause of the
side reactions which were not observed in the reactions with
enones was the water forming in the reaction. To check the
assumption the reaction was carried out in the presence of
TMSCl as water scavenger affording the targeted esters of
dialkylaminoanthranilic acids 12 as the sole products
(Scheme 4).
It should be noted that salicylic acids 14 are not derived
from hydrolysis of the starting enamine 11 so that under
analogous conditions acetoacetic acid esters do not form
salicylates 14. In addition, under the reaction conditions the
transformation of 12 into 13 does not occur.
Figure 2. A perspective view and labeling scheme for the molecule 3a.
Enaminones 16 derivatives of acetylacetone also react with
hexafluoroacetylacetone 1 affording the product without
EWG (Scheme 5). Thus, at room temperature in benzene
both the expected acetophenones 17 and symmetrical
anilines 13 are formed in the reaction. The higher basicity
of dialkylamino group and the easier cleavage of the acetyl
group mean that in the case of pyrrolidine enaminone, the
Figure 3.
Scheme 4. Reagents and conditions: (i) benzene, rt, 3 days; (ii) 1 equiv Me3SiCl, 1 equiv Et3N, benzene, rt, 5 min; (iii) 1 equiv Me3SiCl, 1 equiv Et3N,
benzene, rt, 1 day, 60 8C, 4 h.

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D. M. Volochnyuk et al. / Tetrahedron 61 (2005) 2839–2847
Table 2. Yields of products of the reaction of enamines 11 and 16 with hexafluoroacetylacetone 1a
Enamine
Conditions
Yield (%)
12 or 17
13
14
11a
11b
11c
11a
11b
11c
16a
16b
16c
16a
16b
16c
C6H6, rt, 3 days
C6H6, rt, 3 days
C6H6, rt, 3 days
C6H6, TMSCl, Et3N
C6H6, TMSCl, Et3N
C6H6, TMSCl, Et3N
C6H6, rt, 3 days
C6H6, rt, 3 days
C6H6, rt, 3 days
AcOH, 60 8C, 4 h
AcOH, 60 8C, 4 h
AcOH, 60 8C, 4 h
15
17
39
93
71
69
Traces
26
27
5
32
29
14
—
—
—
—
—
—
—
—
—
Traces
Traces
—
—
—
45
10
6
48
—
—
—
45
47
a Refer according to 19F NMR spectra of reaction mixture.
Scheme 5. Reagents and conditions: (i) benzene, rt, 3 days; (ii) AcOH, 60 8C, 4 h.
expected acetophenone 17a is produced only in trace
amounts. Under acidic conditions, influence of the dialkyl-
amino residue basicity is reduced, so that the sole reaction
products are anilines 13.
forming the corresponding arene hydrates 18 which have
few protonation sites; three of them are noted on Scheme 6.
Hexafluoroacetylacetone 1 as a strong CH-acid itself could
act as a proton source in the reaction mixture. Protonation
by pathway A followed by elimination of water affords
targeted products 12 or 17. Protonation at the oxygen atom
of the enaminone fragment (pathway B) affords iminium
salt 19 which upon hydrolysis gives the corresponding
phenol 14. In addition, protonation at the carbon atom of
enamine fragment forming iminium salt 20 which could
either hydrolize into the corresponding phenol 14 or enter
into ketone cleavage giving symmetrical anilines 13.
Increase of the basicity of the dialkylamino residue
Use of TMSCl in the reaction increases the conversion
of hexafluoroacetylacetone 1 and decreases the yield of
symmetrical anilines 13. At the same time the reaction is
accompanied by many side reactions thus complicating
separation of the targeted products.
We suppose that enaminoesters 11 and enaminoketones 16
like enaminonitriles 2 react with hexafluoroacetylacetone 1
Scheme 6.

D. M. Volochnyuk et al. / Tetrahedron 61 (2005) 2839–2847
2843
1
facilitates protonation by pathways B and C, so that the
number of by-products increases. Actually, the increase of
by-products was observed in series of enaminoesters 11 and
enaminoketones 16.
162 8C. H NMR (acetone-d6): dZ1.99 (4H, br, m, CH2),
2
2.99 and 3.07 (2H, AB-syst, JHHZ16.8 Hz), 3.85 (4H, br,
s, NCH2), 5.73 (1H, s, OH), 5.86 (1H, s, CH). 13C NMR
(DMSO-d6): dZ24.7, 34.5, 51.0, 65.1, 69.4 (2JCF
Z
28.5 Hz), 110.3, 118.9, 123.6 (1JCFZ306.5 Hz), 124.1
(1JCFZ272.1 Hz), 131.6 (2JCFZ28.6 Hz), 157.6. 19F
NMR (acetone): dZK65.1 (3F), K81.3 (3F). IR, nmax
(cmK1): 3500–3200 (br), 2989, 2868, 2191, 1663, 1545,
1271. MS, m/z (%): 326 (MC, 11), 308 (MCKH2O, 14),
307 (22), 280 (37), 257 (MCKCF3, 96), 148 (32), 119 (53),
69 (CFC3 , 39), 55 (45), 42 (86), 41 (100). Anal. calcd for
C13H12F6N2O: C 47.86; H 3.71; N 8.59. Found C 47.92; H
3.65; N 8.60.
3. Conclusions
The reaction of 1,1,1,5,5,5-hexafluoroacetylacetone with
push–pull enamines having a methyl group at the a-position
was investigated. It has been found that the reaction is very
sensitive both to structure of the starting enamines and to
reaction conditions. As a result, a series of bistrifluoro-
methylated dialkylanilines bearing functional groups at the
benzene ring, symmetrical bistrifluoromethylated dialkyl-
anilines and ethyl ester of bistrifluoromethylated salicylic
acid were obtained. Readily available starting materials
and simple synthetic procedures make this method very
attractive and convenient for the synthesis of various
m-bistrifluoromethyl benzenes derivatives, useful building
blocks for organic and medicinal chemistry.
4.3.2. 4-Hydroxy-2-(4-morpholinyl)-4,6-bis(trifluoro-
methyl)-1,5-cyclohexadiene-1-carbonitrile (3c). Enamine
2c (1 g, 6.6 mmol) was dissolved in benzene (10 mL) and to
the solution formed 1 was added (1.37 g, 6.6 mmol). The
reaction mixture was maintained at 40 8C for 2 h and then it
was left at rt overnight. The precipitate formed was filtered
and washed with cyclohexane affording 3c (316 mg, 14%)
1
as a colourless solid. Mp 144–145 8C. H NMR (acetone-
d6): dZ2.98 and 3.05 (2H, AB-syst, 2JHHZ16.8 Hz), 3.67–
3.92 (8H, m, CH2), 5.85 (1H, s, OH), 5.96 (1H, s, CH). 13
C
4. Experimental
4.1. General
NMR (DMSO-d6): dZ33.9, 50.3, 63.8, 66.1, 69.7 (2JCF
Z
28.5 Hz), 112.3, 116.4, 123.6 (1JCFZ306.5 Hz), 124.1
(1JCFZ272.2 Hz), 134.3 (2JCFZ33.0 Hz), 161.7. 19F
NMR (acetone): dZK67.0 (3F), K82.9 (3F). IR, nmax
(cmK1): 3510–3180 (br), 3078, 2919, 2868, 2193 1649,
1547, 1285. Mp 144–145 8C. MS, m/z (%): 342 (MC, 78),
324 (MCKH2O, 56), 273 (MCKCF3, 48), 266 (60), 239
(100), 228 (32), 219 (29), 215 (35), 42 (34). Anal. calcd for
C13H12F6N2O2: C 45.62; H 3.53; N 8.19. Found C 45.65; H
3.56; N 8.22.
All solvents were purified and dried by standard methods.
NMR spectra were recorded on a Varian VXR-300
spectrometer: 1H and 13C (300 and 75.4 MHz, respectively)
with TMS as an internal standard; 19F (282.2 MHz) with
CFCl3 as internal standard. IR spectra were recorded on a
Nexus-470 spectrometer for samples in KBr discs. Mass
spectra were obtained on a ‘HEWLETT–PACKARD’ HP
GC/MS 5890/5972 instrument (EI, 70 eV) by GC inlet or on
a MX-1321 instrument (EI, 70 eV) by direct inlet for the
thermally labile arene hydrates. Microanalyses were
performed in the Microanalytical Laboratory of the Institute
of Organic Chemistry, National Academy of Sciences of
Ukraine. Column chromatography was performed on silica
gel (63–200 mesh, Merck). Silica gel Merck 60F254 plates
were used for TLC. Starting enamines were prepared
according to the literature.17
4.3.3. cis-4,6-Dihydroxy-2-(4-morpholinyl)-4,6-bis(tri-
fluoromethyl)-1-cyclohexene-1-carbonitrile (4c) and
2-(4-morpholinyl)-4,6-bis(trifluoromethyl)-benzonitrile
(5c). To a solution of enamine 2c (5 g, 32.9 mmol) in
benzene (25 mL) was added 1 (6.84 g, 32.9 mmol). The
reaction mixture was maintained at rt for 3 days. The
precipitate formed was filtered affording a mixture of 4c and
3cw1:1. The mixture obtained was dissolved in acetone
(25 mL) and maintained at rt for 7 days (the reaction
mixture was monitored by 19F NMR spectroscopy). After
complete conversion of 3c to 5c, acetone was evaporated in
vacuo and the residue was triturated with CHCl3 (10 mL)
affording 4c (2.7 g, 23%). The CHCl3 was evaporated in
vacuo. The residue was extracted with boiling n-hexane
(10 mL) and the n-hexane was evaporated in vacuo
affording 5c (2.66 g, 25%).
4.2. X-ray crystallography
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with
the Cambridge Crystallographic Data Center as supplemen-
tary publication no. CCDC-235905 (3a) and CCDC-235904
(4c) and can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
C44 1223/336 033; E-mail: deposit@ccdc.cam.ac.uk).
1
Compound 4c. Colourless solid. Mp 175 8C (EtOAc). H
2
NMR (acetone-d6): dZ2.10 (1H, d, JHHZ14.1 Hz), 2.22
2
4
4.3. Interaction of 1 with b-dialkylaminocrotonitriles
(1H, dd, JHHZ14.1 Hz, JHHZ1.5 Hz), 2.78 (1H, d,
2JHHZ18.0 Hz), 3.14 (1H, dd, JHHZ18.0 Hz, JHH
1.5 Hz), 3.48–3.57 (2H, m, CH2), 3.62–3.79 (6H, m,
Z
2
4
4.3.1. 4-Hydroxy-2-(1-pyrrolidinyl)-4,6-bis(trifluoro-
methyl)-1,5-cyclohexadiene-1-carbonitrile (3a). Enamine
2a (5 g, 36.8 mmol) was dissolved in benzene (25 mL) and
to the solution formed 1 was added (7.65 g, 36.8 mmol). The
reaction mixture was maintained at rt overnight. The
precipitate formed was filtered and washed with cyclohex-
ane affording 3a (3.2 g, 27%) as a colourless solid. Mp
CH2), 5.20 (1H, br. s, OH), 5.87 (1H, br. s, OH). 13C
NMR (acetone-d6): dZ34.2, 34.3, 51.1, 67.4, 72.4 (2JCF
30.2 Hz), 74.8 (2JCFZ30.4 Hz), 79.2, 119.1, 126.0 (1JCF
Z
Z
285.4 Hz), 126.2 (1JCFZ284.4 Hz), 161.3. 19F NMR
(acetone): dZ K78.9 (3F), K82.6 (3F). IR, nmax (cmK1):
3384 (br), 3317 (br), 2983, 2933, 2868, 2184, 1555, 1453,

2844
D. M. Volochnyuk et al. / Tetrahedron 61 (2005) 2839–2847
1261. MS, m/z (%): 360 (MC, 16), 291 (MCK CF3, 100).
Anal. calcd for C13H14F6N2O3: C 43.34; H 3.92; N 7.78.
Found C 43.37; H 3.95; N 7.82.
4.3.6. 2,4-Dimethyl-6-oxo-1,6-dihydropyridine-3-carbo-
nitrile (6). To a solution of enamine 2c (1 g, 6.6 mmol) in
benzene (10 mL) was added 1 (1.37 g, 6.6 mmol). The
reaction mixture was refluxed for 4 h. After cooling to rt the
precipitate formed was filtered affording 6 (230 mg, 24%).
The mother liquor was evaporated in vacuo. The residue
was subjected to a column chromatography over silica gel
using EtOAc as eluent affording 5c (598 mg, 28%, Rf
(EtOAc)Z0.68).
Compound 5c. Colourless solid. Mp 127–130 8C (cyclo-
hexane) with sublimation. Rf (EtOAc)Z0.68 1H NMR
(CDCl3): dZ3.33 (4H, t, 3JHHZ4.2 Hz, NCH2), 3.93 (4H, t,
3JHHZ4.2 Hz, NCH2), 7.42 (1H, s, CH), 7.56 (1H, s, CH).
13C NMR (CDCl3): dZ51.0, 65.8, 104.1, 113.5, 114.8,
120.4, 121.6 (1JCFZ275.2 Hz), 122.3 (1JCFZ274.0 Hz),
134.0 (2JCFZ34.2 Hz), 134.1 (2JCFZ32.8 Hz), 157.5. 19F
NMR(CHCl3):dZK63.5(3F), K64.9(3F). IR, nmax (cmK1):
3083, 3052, 2868, 2843, 2228, 1619, 1445, 1395, 1281,
1142, 979. MS, m/z (%): 324 (MC, 34), 266 (57), 239 (100),
219 (32). Anal. calcd for C13H10F6N2O: C 48.16; H 3.11; N
8.64. Found C 48.25; H 3.22; N 8.61
Compound 6. Colourless solid. Mp 293 8C (lit. 294–
296 8C).18 1H NMR (DMSO-d6): dZ2.22 (3H, s, CH3),
2.39 (3H, s, CH3), 6.10 (1H, s, CH), 12.25 (1H, br. s. OH).
MS, m/z (%): 148 (MC, 67), 119 (100), 105 (21), 78 (11), 52
(11), 42 (13).
4.4. Interaction of 1 with b-dialkylaminocrotonoesters
4.3.4. 2-(1-Pyrrolidinyl)-4,6-bis(trifluoromethyl)-benzo-
nitrile (5a). To a solution of 3a (100 mg) in toluene (25 mL)
a few crystals of p-toluenesulfonic acid were added and the
reaction mixture was refluxed for 0.5–1 h (The reaction was
monitored by TLC using EtOAc as eluent). Toluene was
evaporated in vacuo. The residue was extracted with boiling
n-hexane (2 mL) and n-hexane was evaporated in vacuo
affording 5a (88 mg, 93%) as a colourless solid. Mp 96 8C.
Rf (EtOAc)Z0.81. 1H NMR (CDCl3): dZ2.06 (4H, t,
4.4.1. General procedure for synthesis of compounds
12a–c in the presence of TMSCl and Et3N. Procedure A.
To a solution of 1 (1 g, 4.81 mmol) in dry benzene (10 mL)
was added Me3SiCl (4.81 mmol) and Et3N (4.81 mmol).
The reaction mixture was maintained at rt for 5 min.
Enamine 11a–c (4.81 mmol), Me3SiCl (4.81 mmol) and
Et3N (4.81 mmol) was added consecutively. Reaction
mixture was maintained at rt for 1 day and heated at 60 8C
for 4 h. The precipitate formed was filtered off and the
mother liquor was evaporated in vacuo. The residue was
dried and recrystallised from n-hexane affording the
corresponding ethyl ester of benzoic acid (12a–c).
3
3JHHZ6.6 Hz, CH2), 3.71 (4H, t, JHHZ6.6 Hz, NCH2),
7.09 (1H, s, CH), 7.18 (1H, s, CH). 13C NMR (CDCl3):
dZ25.7, 50.9, 93.2, 109.9, 114.9, 116.0, 120.8 (1JCF
Z
272.8 Hz), 124.1 (1JCFZ271.0 Hz), 134.2 (2JCFZ33.3 Hz),
136.6 (2JCFZ31.0 Hz), 151.8. 19F NMR (CHCl3): dZ
K62.2 (3F), K64.1 (3F). IR, nmax (cmK1): 2957, 2875,
2214, 1632, 1481, 1276, 1116, 1085, 1014, 869. MS, m/z
(%): 308 (MC, 50), 307 (58), 289 (20), 280 (100), 245 (44),
219 (20), 188 (14), 69 (13), 42 (12), 41 (12). Anal. calcd for
C13H10F6N2: C 50.66; H 3.27; N 9.09. Found C 50.61; H
3.22; N 9.07.
4.4.2. Ethyl ester 2-(1-pyrrolidinyl)-4,6-bis(trifluoro-
methyl)-benzoic acid (12a). Pale yellow solid (1.59 g,
93%). Mp 48 8C. Rf (EtOAc)Z0.68. 1H NMR (CDCl3): dZ
1.39 (3H, t, 3JHHZ7.2 Hz, CH3), 1.99 (4H, t, 3JHHZ6.6 Hz,
3
CH2), 3.35 (4H, t, JHHZ6.6 Hz, NCH2), 4.37 (2H, q,
3JHHZ7.2 Hz, CH2), 7.08 (1H, s, CH), 7.2 (1H, s, CH). 13
C
NMR (CDCl3): dZ13.8, 25.9, 53.0, 62.6, 109.8, 114.2,
119.1, 121.9 (1JCFZ272.2 Hz), 122.1 (1JCFZ271 Hz),
130.2 (2JCFZ31.2 Hz), 132.3 (2JCFZ32.4 Hz), 146.9,
167.9. 19F NMR (CHCl3): dZK60.8 (3F), K64.2 (3F).
IR, nmax (cmK1): 2984, 2916, 2858, 1725, 1442, 1383, 1279,
1125, 978. MS, m/z (%): 355 (MC, 25), 326 (100), 310 (31),
290 (38), 280 (18), 240 (14), 234 (15), 213 (18), 41 (11).
Anal. calcd for C15H15F6NO2: C 50.71; H 4.26; N 3.94.
Found C 50.75; H 4.31; N 4.01.
4.3.5. 2-(1-Piperidinyl)-4,6-bis(trifluoromethyl)-benzo-
nitrile (5b). To a solution of enamine 2b (1 g, 6.63 mmol)
in benzene (25 mL) was added 1 (1.38 g, 6.63 mmol). The
reaction mixture was maintained at rt for 3 days (the
reaction mixture was monitored by 19F NMR spectroscopy).
The solvent was evaporated in vacuo. The residue was
dissolved in acetone (10 mL) and maintained at rt for 5 days
(the reaction mixture was monitored by 19F NMR
spectroscopy). Acetone was evaporated in vacuo, residue
was extracted with boiling cyclohexane (15 mL) and
maintained overnight. The precipitate formed was filtered
affording 5b (1.03 g, 48%) as a yellow solid. Mp 42 8C. Rf
4.4.3. Ethyl ester 2-(1-piperidinyl)-4,6-bis(trifluoro-
methyl)-benzoic acid (12b). Yellow oil (1.26 g, 71%). Rf
(EtOAc)Z0.62. 1H NMR (CDCl3): dZ1.39 (3H, t, 3JHH
7.2 Hz, CH3), 1.56 (2H, m, CH2), 1.66 (4H, m, CH2), 2.97
Z
1
(EtOAc)Z0.62. H NMR (CDCl3): dZ1.69 (2H, m, CH2),
3
3
3
1.83 (4H, m, CH2), 3.30 (4H, t, JHHZ5.7 Hz, NCH2), 7.4
(4H, t, JHHZ5.4 Hz, NCH2), 4.42 (2H, q, JHHZ7.2 Hz,
CH2), 7.55 (1H, s, CH), 7.59 (1H, s, CH). 13C NMR
(CDCl3): dZ14.1, 24.0, 26.4, 54.4, 62.3, 117.7, 120.1,
121.8, 121.7 (1JCFZ275.2 Hz), 122.3 (1JCFZ274.0 Hz),
132.2 (2JCFZ32.4 Hz), 132.3 (2JCFZ32.4 Hz), 153.8,
166.4. 19F NMR (CHCl3): dZK60.9 (3F), K64.1 (3F).
IR, nmax (cmK1): 2938, 2883, 2853, 1730, 1440, 1390, 1282,
1130, 978. MS, m/z (%): 369 (MC, 18), 340 (100), 324 (24),
294 (15), 97 (10), 69 (14), 57 (24), 55 (39), 43 (20), 41 (28).
Anal. calcd for C16H17F6NO2: C 52.04; H 4.64; N 3.79.
Found C 51.87; H 4.24; N 3.82.
(1H, s, CH), 7.46 (1H, s, CH). 13C NMR (CDCl3): dZ23.8,
25.9, 53.2, 105.3, 114.0, 114.5, 119.3, 121.6 (1JCF
272.8 Hz), 123.7 (1JCFZ271.3 Hz), 135.2 (2JCF
Z
Z
34.2 Hz), 135.9 (2JCFZ33.5 Hz), 159.1. 19F NMR
(CHCl3): dZK63.5 (3F), K64.9 (3F). IR, nmax (cmK1):
2950, 2858, 2802, 2227, 1620, 1445, 1395, 1280, 1141, 980.
MS, m/z (%): 322 (MC, 87), 321 (100), 293 (57), 281 (29),
245 (18), 239 (28), 84 (28), 69 (37), 55 (16), 43 (30), 42
(24), 41 (36). Anal. calcd for C14H12F6N2: C 52.18; H 3.75;
N 8.69. Found C 52.25; H 3.72; N 8.65.

D. M. Volochnyuk et al. / Tetrahedron 61 (2005) 2839–2847
2845
4.4.4. Ethyl ester 2-(4-morpholinyl)-4,6-bis(trifluoro-
methyl)-benzoic acid (12c). Colourless solid (1.23 g,
4.5. Interaction of 1 with b-enaminones
1
69%). Mp 44 8C. Rf (EtOAc)Z0.55. H NMR (CDCl3):
4.5.1. 1-[3,5-Bis(trifluoromethyl)phenyl]-pyrrolidine
(13a). To a solution of enamine 16a (1 g, 6.54 mmol) in
acetic acid (20 mL) was added 1 (1.36 g, 6.54 mmol). The
reaction mixture was heated at 60 8C for 4 h. Solvent was
evaporated in vacuo and residue was crystallized from
mixture methanol/water K1:1 affording 13a (370 mg, 20%)
as a colourless solid. Mp 63 8C. Rf (EtOAc)Z0.58. 1H NMR
3
3
dZ1.4 (3H, t, JHHZ7.2 Hz, CH2), 3.04 (4H, t, JHH
Z
4.5 Hz, NCH2), 3.8 (4H, t, 3JHHZ4.5 Hz, OCH2), 4.44 (2H,
q, JHHZ7.2 Hz, CH2), 7.6 (1H, s, CH), 7.68 (1H, s, CH).
3
13C NMR (CDCl3): dZ14.1, 53.2, 53.3, 67.1, 118.8, 121.6
(1JCFZ275.2 Hz), 121.8, 122.3 (1JCFZ274.0 Hz), 124.2,
132.9 (2JCFZ32.8 Hz), 133.3 (2JCFZ34.7 Hz), 151.9,
165.9. 19F NMR (CHCl3): dZK61.0 (3F), K64.1 (3F).
IR, nmax (cmK1): 3058, 2996, 2925, 2863, 1732, 1442, 1387,
1282, 1129, 978. MS, m/z (%): 371 (MC, 27), 352 (17), 340
(18), 328 (52), 298 (100), 284 (73), 268 (70), 240 (55), 213
(44), 194 (23), 163 (24), 143 (20), 59 (37), 45 (25). Anal.
calcd for C15H15F6NO3: C 48.53; H 4.07; N 3.77. Found C
48.47; H 4.02; N 3.82.
3
(CDCl3): dZ2.64 (4H, t, JHHZ6.3 Hz, CH2), 3.34 (4H, t,
3JHHZ6.3 Hz, NCH2), 6.85 (2H, s, CH), 7.08 (1H, s, CH).
13C NMR (CDCl3): dZ25.4, 47.7, 107.9, 110.7, 125.2
(1JCFZ270.3 Hz), 131.9 (2JCFZ32.2 Hz), 147.9. 19F NMR
(CHCl3): dZK64.7. IR, nmax (cmK1): 2984, 2916, 2858,
1623, 1499, 1481, 1425, 1275, 1162, 1123, 1012, 853, 701,
682. MS, m/z (%): 283 (MC, 61), 282 (100), 264 (21), 240
(32), 227 (71), 213 (40), 163 (13), 41 (10). Anal. calcd for
C12H11F6N: C 50.89; H 3.91; N 4.95. Found C 50.92; H
4.02; N 4.91.
4.4.5. Ethyl ester 2-hydroxy-4,6-bis(trifluoromethyl)-
benzoic acid (14). To a solution of enamine 11a (5 g,
27.4 mmol) in benzene (75 mL) was added 1 (5.68 g,
27.4 mmol). The reaction mixture was maintained at rt for 3
days (the reaction mixture was monitored by 19F NMR
spectroscopy). The solvent was evaporated in vacuo. The
residue obtained was placed in short silica gel column and
washed with EtOAc (4!25 mL). EtOAc was evaporated in
vacuo and the residue obtained was subjected to fractional
distillation affording 14 (2.23 g, 27%) and 12a (0.68 g, 7%).
4.5.2. 1-[3,5-Bis(trifluoromethyl)phenyl]-piperidine
(13b). Enaminone 16b (1 g, 5.98 mmol) was dissolved in
acetic acid (20 mL) and to the solution formed 1 was added
(1.24 g, 5.98 mmol). The reaction mixture was maintained
at rt overnight and then heated at 60 8C for 4 h. The solvent
was evaporated in vacuo. The residue was extracted with
boiling n-hexane (15 mL). The hexane was evaporated in
vacuo and the residue was crystallized from methanol
affording 13b (370 mg, 21%) as a colourless solid. Mp 60–
1
Colourless solid. Mp 24 8C. Rf (EtOAc)Z0.56. H NMR
(CDCl3): dZ1.44 (3H, t, 3JHHZ7.2 Hz, CH3), 4.49 (2H, q,
3JHHZ7.2 Hz, CH2), 7.48 (1H, s, CH), 7.53 (1H, s, CH),
10.8 (1H, br s, OH). 13C NMR (CDCl3): dZ13.5, 63.3,
1
62 8C. Rf (EtOAc)Z0.64. H NMR (CDCl3): dZ3.25 (4H,
3
3
t, JHHZ4.8 Hz), 3.87 (4H, t, JHHZ4.8 Hz), 7.24 (2H, s,
CH), 7.32 (1H, s, CH). 13C NMR (CDCl3): dZ24.0, 25.4,
114.6, 115.3, 119.4, 124.3 (1JCFZ270.5 Hz), 124.5 (1JCF
Z
49.5, 111.1, 114.8, 125.6 (1JCFZ271.5 Hz), 132.4 (2JCF
Z
273.2 Hz), 131.9 (2JCFZ31.7 Hz), 135.6 (2JCFZ32.9 Hz),
161.7, 168.1. 19F NMR (CHCl3): dZ59.6 (3F), K65.2 (3F).
IR, nmax (cmK1): 3400–2800 (br), 2991, 2944, 1737 (sh),
1683, 1445, 1380, 1324, 1276, 1139, 1012, 962, 885, 730.
MS, m/z (%): 302 (MC, 23), 256 (100), 228 (40), 209 (27),
200 (17), 181 (14). Anal. calcd for C11H8F6O3: C 43.72; H
2.67; Found C 43.58; H 2.69.
31.8 Hz), 152.2. 19F NMR (CHCl3): dZK64.2. IR, nmax
(cmK1): 3077, 3062, 3011, 2938, 2883, 2853, 1619,
1480, 1413, 1283, 1141, 1132, 1024, 953, 859, 699,
682. MS, m/z (%): 297 (MC, 61), 296 (100), 278 (19),
256 (28), 240 (49), 213 (32), 163 (11). Anal. calcd for
C13H13F6N: C 52.53; H 4.41; N 4.71. Found C 52.25; H
4.36; N 4.52.
4.5.3. 4-[3,5-Bis(trifluoromethyl)phenyl]-morpholine
(13c). To
4.4.6. General procedure for interaction of 1 with
b-dialkylaminocrotonoesters. To a solution of enamines
11a–c (9.71 mmol) in benzene (30 mL) was added 1 (2 g,
9.71 mmol). The reaction mixture was maintained at rt for 3
days (the reaction mixture was monitored by 19F NMR
spectroscopy). The solvent was evaporated in vacuo. The
residue obtained was placed in a short silica gel column and
washed with EtOAc (2!25 mL). EtOAc was evaporated in
vacuo and the residue obtained was carefully dried in vacuo
dissolved in anhyd n-hexane (30 mL). To the stirred
solution obtained NaH (240 mg, 10 mmol) was carefully
added and the solution was maintained until hydrogen
evolution had stopped. The precipitate formed was filtered
off under argon. The mother liquior was evaporated in vacuo
and the residue obtained was subjected to a column
chromatography over silica gel using EtOAc as eluent
affording 12a–c. The precipitate obtained was suspended in
anhydrous CH2Cl2 (25 mL) and to the stirred suspension
water (5 mL) was added dropwise and then aq HCl (30%,
1 mL) was added dropwise. The organic layer was separated
and dried over Na2SO4. CH2Cl2 was evaporated in vacuo
affording 14 (purity O95%).
a solution of enaminone 16c (0.81 g,
4.81 mmol) in acetic acid (20 mL) was added 1 (1 g,
4.81 mmol). The reaction mixture was heated at 60 8C for
4 h. The solvent was evaporated in vacuo and residue was
crystallized from methanol affording 13c (0.268 g, 38%) as
1
colourless solid. Mp 123 8C. Rf (i-PrOH)Z0.39. H NMR
(CDCl3): dZ1.63–1.72 (6H, m, 3CH2), 3.27 (4H, t, 3JHH
Z
4.8 Hz), 7.23 (3H, s, CH). 13C NMR (CDCl3): dZ48.3,
66.5, 112.4, 114.4, 125.3 (1JCFZ270.9 Hz), 132.2 (2JCF
Z
32.1 Hz), 151.7.19F NMR (CHCl3): dZK64.2. IR, nmax
(cmK1): 3082, 3060, 2983, 2918, 2847, 1617, 1487, 1405,
1286, 1170, 1114, 970, 857, 691, 683. MS, m/z (%): 299
(MC, 41), 280 (14) 241 (100), 213 (27). Anal. calcd for
C12H11F6NO: C 48.17; H 3.71; N 4.68. Found C 48.21; H
3.73; N 4.56.
4.5.4. 1-[2-(1-Piperidinyl)-4,6-bis(trifluoromethyl)-
phenyl]-ethanone (17b). Enaminone 16b (1 g,
5.99 mmol) was dissolved in anhyd benzene (10 mL) and
to the solution formed 1 (1.24 g, 5.99 mmol) was added. The
reaction mixture was maintained at rt overnight. Benzene

2846
D. M. Volochnyuk et al. / Tetrahedron 61 (2005) 2839–2847
was evaporated in vacuo. The residue was dissolved in
methanol. To the solution formed a few drops of water was
added (w0.1 mL). The precipitate formed was filtered
affording 17b (406 mg, 20%) as a colourless solid mp 88 8C.
Rf (EtOAc)Z0.73. 1H NMR (CDCl3): dZ1.54–1.6 (2H, m,
CH2), 1.66–1.71 (4H, m, CH2) 2.56 (3H, s, CH3), 2,92 (4H,
t, 3JHHZ5.4 Hz, NCH2), 7.57 (1H, s, CH), 7.63 (1H, s, CH).
13C NMR (CDCl3): dZ23.7, 26.2, 31.1, 54.6, 118.1, 121.1,
124.1 (1JCFZ271.9 Hz), 124.4 (1JCFZ270.8 Hz), 128.3
(2JCFZ32.1 Hz), 131.2 (2JCFZ33.0 Hz), 140.8, 152.7,
202.6. 19F NMR (CHCl3): dZK60.1 (3F), K64.1 (3F).
IR, nmax (cmK1): 2950, 2858, 2802, 1710, 1386, 1273, 1131,
963, 897. MS, m/z (%): 339 (MC, 47), 324 (100), 306 (39),
268 (25), 248 (17), 238 (27), 213 (16), 43 (26). Anal. calcd
for C15H15F6NO: C 53.1; H 4.46; N 4.13. Found C 53.06; H
4.41; N 4.06.
References and notes
1. (a) Fluorine in Bioorganic Chemistry; Filler, R., Kobayasi, Y.,
Yagupolskii, L. M., Eds.; Elseiver: Amsterdam, 1993.
(b) Filler, R. Fluorine Containing Drugs in Organofluorine
Chemicals and Their Industrial Application; Pergamon: New
York, 1979; (Chapter 6). (c) Hudlicky, M. Chemistry of
Organic Fluorine Compounds; Ellis Horwood: Chichester,
1992.
2. For recent examples, see: (a) Arndt-Rosenau, M.; Hoch, M.;
Sundermeyer, J.; Kipke, J. EP-16983, 2002; Chem. Abstr.
2003, 138, 170656. (b) Liedtke, J.; Loss, S.; Widauer, C.;
Grutzmacher, H. Tetrahedron 2000, 56, 143–156.
3. For recent examples of using derivatives of 3,5-bistrifluoro-
methylaniline, see: (a) Tagmose, T. M.; Zaragoza, F.; Boonen,
H. C. M.; Worsaae, A.; Mogensen, J. P.; Nielsen, F. E.; Jensen,
A. F.; Hansen, J. B. Bioorg. Med. Chem. 2003, 11, 931–940.
(b) Bongartz, J.-P.; Stokbroekx, R.; der Aa, M. V.; Luyckx,
M.; Willems, M.; Ceusters, M.; Meerpoel, L.; Smets, G.;
Jansen, T.; Wouters, W.; Bowden, C.; Valetta, L.; Herb, M.;
Tominovich, R.; Tuman, R. Bioorg. Med. Chem. Lett. 2002,
12, 589–592. (c) Dolezal, M.; Miletin, M.; Kunes, J.; Kralova,
K. Molecules 2002, 7, 363–373. (d) Tagmose, T. M.;
Mogensen, J. P.; Agerholm, P. C.; Arkhammar, P. O. G.;
Wahl, P.; Worsaae, A.; Hansen, J. B. Bioorg. Med. Chem. Lett.
2001, 11, 1749–1752. (e) Wilson, L. J.; Morris, T. W.; Wu, Q.;
Renick, P. J.; Parker, C. N.; Davis, M. C.; McKeever, H. D.;
Hershberger, P. M.; Switzer, A. G.; Shrum, G.; Sunder, S.; et al
Bioorg. Med. Chem. Lett. 2001, 11, 1149–1152. (f) Palanki,
M. S. S.; Erdman, P. E.; Gayo-Fung, L. M.; Shevlin, G. I.;
Sullivan, R. W.; Suto, M. J.; Goldman, M. E.; Ransone, L. J.;
Bennett, B. L.; Manning, A. M. J. Med. Chem. 2000, 43,
3995–4004.
Note. When the residue after evaporating off benzene from
the reaction mixture was subjected to a column chroma-
tography over silica gel using EtOAc as eluent we would
obtain 13b (110 mg, 6%) and 17b (400 mg, 20%).
4.5.5. 1-[2-(4-Morpholinyl)-4,6-bis(trifluoromethyl)-
phenyl]-ethanone (17c). Enaminone 16c (1 g, 5.99 mmol)
was dissolved in anhydrous benzene (25 mL) and to a
solution formed 1 (1.24 g, 5.99 mmol) was added. The
reaction mixture was maintained at rt overnight. The
benzene was evaporated in vacuo. The residue was
dissolved in methanol. To a solution formed a few drops
of water was added (w0.1 mL). The precipitate formed was
filtered affording 17c (430 mg, 21%) as a colourless solid
1
Mp 56 8C. Rf (i-PrOH)Z0.74. H NMR (CDCl3): dZ2.58
(3H, s, CH3), 2.99 (4H, t, 3JHHZ4.5 Hz, NCH2), 3.81 (4H, t,
3JHHZ4.5 Hz OCH2), 7.60 (1H, s, CH), 7.69 (1H, s, CH).
13C NMR (CDCl3): dZ31.3, 53.4, 66.9, 119.1, 121.5, 124.4
4. For recent examples of using derivatives of 3,5-bistrifluoro-
methylphenol, see (a) Ryckmans, T.; Balancon, L.; Berton, O.;
Genicot, C.; Lamberty, Y.; Lallemand, B.; Pasau, P.; Pirlot,
N.; Quere, L.; Talaga, P. Bioorg. Med. Chem. Lett. 2002, 12,
261–264. (b) Malamas, M. S.; Sredy, J.; Gunawan, I.; Mihan,
B.; Sawicki, D. R.; Seestaller, L.; Sullivan, D.; Flam, B. R.
J. Med. Chem. 2000, 43, 995–1010.
(1JCFZ275.0 Hz), 124.7 (1JCFZ271.3 Hz), 128.1 (2JCF
Z
28.9 Hz), 131.7 (2JCFZ33.5 Hz), 141.2, 151.0, 202.2. 19F
NMR(CHCl3):dZK59.4(3F), K62.0(3F). IR, nmax (cmK1):
3077, 2984, 2847, 1707, 1439, 1380, 1274, 1142, 971. MS,
m/z (%): 341 (MC, 48), 326 (39), 296 (19), 280 (24), 268
(100), 255 (27), 240 (19), 213 (17), 43 (44). Anal. calcd for
C14H13F6NO2: C 49.27; H 3.84; N 4.10. Found C 49.19; H
3.91; N 4.12.
5. Ross, S. D.; Markarian, M.; Schwarz, M. J. Am. Chem. Soc.
1953, 75, 4967–4969.
6. (a) Harris, M. S.; Geis, O.; Buchwald, S. L. J. Org. Chem.
1999, 64, 6019–6022. (b) Antane, S. Synth. Commun. 2003,
33, 2145–2150.
7. Dmowski, W.; Piasecka-Maciejewska, K. J. Fluorine Chem.
1996, 78, 59–64.
Note. When the residue after evaporating off benzene from
the reaction mixture was subjected to a column chroma-
tography over silica gel using i-PrOH as eluent we would
obtain 17c (490 mg, 24%) and then after washing of column
with EtOAc we would obtain 13c (72 mg, 4%).
8. (a) Sloop, J. C.; Bumgardner, C. L.; Loehle, W. D. J. Fluorine
Chem. 2002, 118, 135–148. (b) Singh, S. P.; Kumar, D.; Batra,
H.; Rozas, I.; Elguero, J. Can. J. Chem. 2000, 78, 1109–1120.
9. Volochnyuk, D. M.; Pushechnikov, A. O.; Krotko, D. G.;
Sibgatulin, D. A.; Kovaleva, S. A.; Tolmachev, A. A.
Synthesis 2003, 1531–1540 and references cited therein.
10. (a) Burgart, Ya. V.; Kuzueva, O. G.; Pryadeina, M. V.; Kappe,
C. O.; Saloutin, V. I. Russ. J. Org. Chem. 2001, 37, 869–880.
(b) Chu-Moyer, M. Y.; Ballinger, W. E.; Beebe, D. A.; Berger,
R.; Coutcher, J. B.; Day, W. W.; Li, J.; Mylari, B. L.; Oates,
P. J.; Weekly, R. M. J. Med. Chem. 2002, 45, 511–528.
11. Ohkura, H.; Berbasov, D. O.; Soloshonok, V. A. Tetrahedron
Lett. 2003, 44, 2417–2420.
Acknowledgements
The authors acknowledge A. V. Turov, S. A. Alekseev
(Department of Chemistry of Kyiv National Taras
Shevchenko University), A. V. Mazepa (Bogatsky Physi-
co-Chemical Institute, National Academy of Sciences
of Ukraine, Department of Molecular Structure) and
Yu. V. Kuzmenko (Central Customs Laboratory of National
Customs Service of Ukraine) for spectral measurement.
12. Skryabina, Z. E.; Burgart, Ya. V.; Saloutin, V. I. Bull. Acad.
Sci. USSR Div. Chem. Sci. 1991, 40, 788–794.
13. Volochnyuk, D. M.; Kostyuk, A. N.; Sibgatulin, D. A.;

D. M. Volochnyuk et al. / Tetrahedron 61 (2005) 2839–2847
2847
Chernega, A. N.; Pinchuk, A. M.; Tolmachev, A. A.
Tetrahedron 2004, 60, 2361–2371.
16. Padva, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org.
Chem. 1997, 62, 4088–4096.
14. Volochnyuk, D. M.; Kostyuk, A. N.; Sibgatulin, D. A.;
Petrenko, A. E. Synthesis 2004, 2545–2549.
17. (a) Hickmott, P. W.; Sheppard, G. J. Chem. Soc. (C) 1971,
1358–1364. (b) Dedina, J.; Kuthan, J.; Palecek, J.; Schraml, J.
Collect. Czech. Chem. Commun. 1975, 40, 3476–3490.
18. Yalisheva, N. Z.; Chistyakov, V. V.; Granik, V. G. Khim.
Heterocycl. Compd. (Engl. Transl.) 1986, 22, 70–73.
15. (a) Staroscik, J.; Rickborn, B. J. Am. Chem. Soc. 1971, 93,
3046–3047. (b) Brion, F. Tetrahedron Lett. 1982, 23,
5299–5302.