Reaction of α,β-unsaturated trifluoromethyl ketones with cyclic enamines

Article abstract of DOI:10.1023/B:RUCB.0000030821.56661.44

The reactions of α,β-unsaturated trifluoromethyl ketones containing aromatic and heteroaromatic substituents with 1-morpholinocyclopentene, 1-morpholinocyclohexene, and 1-methyl-4-morpholino-1,2,5,6-tetrahydropyridine were studied. The reactions proceeded stereospecifically to give the corresponding bicyclo[3.2.1]octane, bicyclo[3.3.1]nonane, and azabicyclo[3.3.1]nonane derivatives.

Full text of DOI:10.1023/B:RUCB.0000030821.56661.44

Russian Chemical Bulletin, International Edition, Vol. 53, No. 2, pp. 435—442, February, 2004
435
Reaction of α,βꢀunsaturated trifluoromethyl ketones with
cyclic enamines
V. G. Nenajdenko,ꢀ S. V. Druzhinin, and E. S. Balenkova
Department of Chemistry, M. V. Lomonosov Moscow State University,
Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (095) 932 8846. Eꢀmail: nen@acylium.chem.msu.ru
The reactions of α,βꢀunsaturated trifluoromethyl ketones containing aromatic and
heteroaromatic substituents with 1ꢀmorpholinocyclopentene, 1ꢀmorpholinocyclohexene, and
1ꢀmethylꢀ4ꢀmorpholinoꢀ1,2,5,6ꢀtetrahydropyridine were studied. The reactions proceeded steꢀ
reospecifically to give the corresponding bicyclo[3.2.1]octane, bicyclo[3.3.1]nonane, and
azabicyclo[3.3.1]nonane derivatives.
Key words: unsaturated trifluoromethyl ketones, enamines, stereochemistry, cycloaddition.
In recent years, considerable attention has been given
to the development of new procedures for the synthesis of
fluorineꢀcontaining compounds, which are often used in
both medicine and agricultural chemistry.1,2 α,βꢀUnsatꢀ
urated trifluoromethyl ketones serve as convenient buildꢀ
ing blocks for the introduction of the trifluoromethyl group
into different classes of acyclic, carbocyclic, and heteroꢀ
cyclic compounds. However, their properties have not
been adequately investigated.3,4
The reaction of the only unsaturated trifluoromethyl
ketone, viz., 4ꢀethoxyꢀ1,1,1ꢀtrifluorobutꢀ3ꢀenꢀ2ꢀone (1a),
with 1ꢀpyrrolidinocyclohexene in anhydrous Et2O was
described in the literature.5 The reaction gave rise to
4ꢀethoxyꢀ2ꢀhydroxyꢀ2ꢀtrifluoromethylbicyclo[3.3.1]noꢀ
nanꢀ9ꢀone as a single diastereomer (Scheme 1).
afforded a product (in a nearly quantitative yield), which
was identified as 1,1,1ꢀtrifluoroꢀ4ꢀ(morpholinꢀ4ꢀyl)butꢀ
3ꢀenꢀ2ꢀone (4), instead of the expected bicyclic hydroxy
ketone 3a. Apparently, this reaction pathway is associated
with the influence of the polar solvent, and the reaction
proceeds at the nitrogen atom of the amino fragment of
enamine rather than at the αꢀcarbon atom.
It is known that α,βꢀunsaturated trifluoromethyl keꢀ
tones containing a substituent, which is capable of being
eliminated, at position 4 can differ radically in the reacꢀ
tivity and the reaction pathway from α,βꢀunsaturated
trifluoromethyl ketones devoid of such substituents.4 In
this connection, we studied the reactions of ketones conꢀ
taining aryl and hetaryl substituents6—8 with various cyꢀ
clic enamines.
We chose 1,1,1ꢀtrifluoroꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀone
(1c) and 1ꢀmorpholinocyclohexene (2b) as model subꢀ
strates. The reactions were carried out in 96% EtOH
at ≈20 °C followed by treatment of the reaction mixture
with an aqueous NH4Cl solution to hydrolyze iminium
intermediates. Bicyclic ketone 3c was isolated from the
reaction mixture. Therefore, the reaction is not finished
at the step of formation of the Michael adduct and results
in cyclization of the iminium intermediate to give a biꢀ
cyclic derivative (Scheme 3).
Scheme 1
Bicyclic hydroxy ketone 3c was isolated as a single
diastereomer. To confirm the structure and reveal the
orientations of the substituents, we carried out Xꢀray difꢀ
fraction analysis and established that the phenyl substituꢀ
ent and the hydroxy group are in the axial positions,
whereas the trifluoromethyl group is in the equatorial poꢀ
sition (Fig. 1). It was found that there is no intramolecuꢀ
lar hydrogen bond between the proton of the hydroxy
group and the oxygen atom of the carbonyl group, whereas
the proton of the hydroxy group and the oxygen atom of
In all cases, the reactions of trifluoromethyl ketones 1a
and 1b with enamines 2a—c in aqueous EtOH (Scheme 2)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 416—422, February, 2004.
1066ꢀ5285/04/5302ꢀ0435 © 2004 Plenum Publishing Corporation

436
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 2, February, 2004
Nenajdenko et al.
Scheme 2
these two forms, the transition state B gives a product
with the aboveꢀmentioned stereochemistry. As can be seen
from the projection of B, this transition state is characterꢀ
ized by minimum steric hindrances caused by interacꢀ
tions between the trifluoroacetyl group and the amino
moiety of enamine, due to which the reaction proceeding
through this intermediate affords a product with the axial
orientation of the phenyl substituent.
1
R
1
R
2
X
a
b
c
d
OEt
OBu
Ph
4ꢀMeC6H4
f
3ꢀMeOC6H4
3,5ꢀ(MeO)2C6H3
2ꢀthienyl
a
b
c
—CH2—
—(CH2)2—
—CH2—N(Me)—
g
h
i
3ꢀindolyl
e
3ꢀMeC6H4
j
Therefore, the first step of this reaction, viz., the
Michael addition, is kinetically controlled. The second
step, which is responsible for the orientation of the hydrꢀ
oxy group, also proceeds under kinetically controlled conꢀ
ditions, because the bulky CF3 group is in the equatorial
position. We demonstrated that hydrolysis of the reaction
mixture with 6 M hydrochloric acid afforded a mixture of
diastereomers of compound 3c. Therefore, the formation
of the diastereomer with the axial orientation of the pheꢀ
nyl group is attributed to the kinetic control over the
reaction.
We also carried out the reactions of 1ꢀmorpholinoꢀ
cyclohexene (2b) with ketones 1d—j. At ≈20 °C, these
reactions proceeded rather slowly and necessitated reꢀ
fluxing (except for the reactions with ketones 1i and 1j
containing the 3ꢀindolyl and 2ꢀmethylindolꢀ3ꢀyl substituꢀ
ents, respectively; these reactions did not proceed due,
apparently, to the high electronꢀdonating ability of these
substituents and the bulkiness of the substituent at the
β position). In all cases, the reactions proceeded steꢀ
reospecifically to give the only diastereomer in a virtually
quantitative yield. The configuration of the latter is, apꢀ
parently, analogous to that of compound 3c. The elecꢀ
tronꢀdonating properties of the substituent in the starting
trifluoromethyl ketone have only a slight effect on the
yield of the reaction product but influence substantially
the reaction time.
i. EtOH, H2O, 20 °C.
the carbonyl group of the adjacent molecule are involved
in an intermolecular hydrogen bond.
To compare the reactivities of enamines, we carried
out the reactions with 1ꢀmorpholinocyclopentene (2a)
and 1ꢀmethylꢀ4ꢀmorpholinoꢀ1,2,5,6ꢀtetrahydropyridine
(2c), which proceeded analogously to that with 2b to give
the corresponding bicyclic products 5 and 6 (see Scheme 2,
Table 1).
As expected, due to a higher steric strain of the ring,
1ꢀmorpholinocyclopentene (2a) exhibits much higher reꢀ
activity compared to that of morpholinocyclohexene (2b)
and is involved in the reaction at ≈20 °C. 1ꢀMethylꢀ4ꢀ
morpholinoꢀ1,2,5,6ꢀtetrahydropyridine (2c) is also more
In addition, the 2D 1H—1H COSY NMR spectrum of
compound 3c completely confirms the assignment of the
1
protons in the H NMR spectrum and is consistent with
the threeꢀdimensional structure established by Xꢀray difꢀ
fraction analysis.
To explain the fact that the phenyl substituent in comꢀ
pound 3c is in the axial position rather than in the enerꢀ
getically more favorable equatorial position, two transiꢀ
tion states (A and B) were discussed in the study.5 Of

Reaction of α,βꢀunsaturated CF3 ketones
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 2, February, 2004
437
Scheme 3
reactive than 2b. The reactions of both these enamines
proceeded stereospecifically to give the corresponding biꢀ
cyclic ketones 5 and 6 in high yields. For these enamines,
the dependence of the reaction rate on the electronꢀdoꢀ
nating properties of the substituent in the starting ketone
is analogous to that observed for 1ꢀmorpholinocycloꢀ
hexene (2b).
To summarize, we demonstrated that the reactions
of unsaturated trifluoromethyl ketones with enamines
proceed stereospecifically to form the corresponding
derivatives of bicyclic hydroxy ketones. The structures
of these compounds and the orientations of the funcꢀ
tional groups were established by Xꢀray diffraction
analysis.
Fig. 1. Structure of compound 3c based on Xꢀray diffraction analysis.

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Russ.Chem.Bull., Int.Ed., Vol. 53, No. 2, February, 2004
Nenajdenko et al.
Table 1. Reactions of trifluoromethyl ketones 1c—j* with enamines 2a—c
Starting
3
5
6
ketone, R
τ/h
refluxing
Yield
(%)
τ/h
Yield
(%)
τ/h
Yield
(%)
1с, Ph
6—7
14
12
16
16
95
83
98
92
99
87
***
6
99
82
94
88
87
99
52
8
70
61
**
79
50
66
51
1d, 4ꢀMeC6H4
1e, 3ꢀMeC6H4
1f, 3ꢀMeOC6H4
1g, 2,5ꢀ(MeO)2C6H4
1h, 2ꢀthienyl
1i, 3ꢀindolyl
14
12
16
48
16
48
12
**
16
50
14
50
48
***
* The reaction with 1j did not proceed.
** The reaction was not carried out.
*** The reaction did not proceed.
4ꢀMeC6H4, H(2´), H(6´), J = 7.7 Hz); 7.54 (d, 2 H, 4ꢀMeC6H4,
(H(3´), H(5´), J = 7.7 Hz); 7.94 (d, 1 H, CH=CHCO,
J = 15.9 Hz). 13C NMR (CDCl3), δ: 21.33 (Me); 115.3
(CH=CHCO); 116.5 (q, CF3, J = 291.5 Hz); 129.2, 129.8,
130.6, 143.3 (4ꢀMeC6H4); 150.0 (CH=CHCO); 179.8 (q, C=O,
J = 35.1 Hz).
Experimental
The 1H, 13C, and COSY NMR spectra of compound 3c were
recorded on a Bruker Avanceꢀ600 spectrometer (at 600 and
150 MHz for 1H and 13C, respectively) in CDCl3, CD3CN, or
(CD3)2SO with Me4Si as the internal standard. The 1H and
13C NMR spectra for all other compounds were measured on a
Varian VXRꢀ400 spectrometer (at 400 and 100 MHz, respecꢀ
tively) in CDCl3, CD3CN, or (CD3)2SO with Me4Si as the
internal standard. The IR spectra were recorded on a URꢀ20
spectrometer in Nujol mulls. The TLC analysis was performed
on Silufol UVꢀ254 plates; visualization was carried out with an
acidified solution of KMnO4 and iodine vapor. 1,1,1ꢀTrifluoroꢀ
4ꢀdimethylaminobutꢀ3ꢀenꢀ2ꢀone was synthesized according to
a procedure described earlier.6
1,1,1ꢀTrifluoroꢀ4ꢀ(3ꢀmethylphenyl)butꢀ3ꢀenꢀ2ꢀone (1e). The
yield was 65%, paleꢀyellow oil. Found (%): C, 63.44; H, 5.01.
C12H11F3O. Calculated (%): C, 63.16; H, 4.86. IR, ν/cm–1
:
1
1735 (C=O); 1630 (C=C). H NMR (CDCl3), δ: 2.40 (s, Me);
7.00 (d, 1 H, CH=CHCO, J = 15.9 Hz); 7.28—7.37 (m, 2 H, 3ꢀ
MeC6H4, H(2´), H(4´)); 7.42—7.46 (m, 2 H, 3ꢀMeC6H4, H(5´),
H(6´)); 7.94 (d, 1 H, CH=CHCO, J = 15.9 Hz). 13C NMR
(CDCl3), δ: 20.9 (Me); 116.1 (CH=CHCO); 116.4 (q, CF3, J =
291.5 Hz); 126.4, 128.5, 128.9, 129.6, 133.1, 138.9 (3ꢀMeC6H4);
150.0 (CH=CHCO); 179.7 (q, C=O, J = 35.1 Hz).
Synthesis of α,βꢀunsaturated trifluoromethyl ketones (genꢀ
eral procedure).6 A solution of BuLi (0.1 mol) in anhydrous
THF (200 mL) cooled to –70 °C was placed in a threeꢀneck
flask, which was flameꢀdried in an argon flow and equipped with
an internal thermometer and a dropping funnel, and a solution
of the corresponding aryl bromide (0.1 mol) in anhydrous THF
(20 mL) was added dropwise. The resulting suspension of
aryllithium was stirred at this temperature for 30 min. Then a
solution of 1,1,1ꢀtrifluoroꢀ4ꢀdimethylaminobutꢀ3ꢀenꢀ2ꢀone
(0.1 mol) in anhydrous THF (20 mL) was added dropwise to the
reaction mixture, the temperature of no higher than –60 °C
being maintained. Then the temperature of the reaction mixture
was raised to +10 °C during ≈1 h and 4 M HCl (60 mL) was
added. The mixture was stirred at ≈20 °C for 30 min, the upper
organic layer was separated, and the lower aqueous layer was
extracted with CH2Cl2 (3×80 mL). The combined extracts were
dried with Na2SO4, the solution was concentrated, and the reꢀ
action product, which was obtained as a dark oil, was chromaꢀ
tographed on a column with silica gel (hexane—AcOEt,
15 : 1—3 : 1, as the eluent).
1,1,1ꢀTrifluoroꢀ4ꢀ(3ꢀmethoxyphenyl)butꢀ3ꢀenꢀ2ꢀone (1f).
The yield was 67%, paleꢀyellow oil. Found (%): C, 59.18;
H, 4.67. C12H11F3O2. Calculated (%): C, 59.02; H, 4.54. IR,
ν/cm–1: 1730 (C=O); 1630 (C=C). 1H NMR (CDCl3, δ: 3.86
(s, OMe); 6.99 (dd, 1 H, CH=CHCO, J = 15.9 Hz, J = 0.8 Hz);
7.04 (ddd, 1 H, 3ꢀMeOC6H4, H(2´), J = 8.0 Hz; J = 2.5 Hz; J =
0.8 Hz); 7.13 (t, 1 H, 3ꢀMeOC6H4, H(4´), J = 2.5 Hz); 7.23 (dt,
1 H, 3ꢀMeOC6H4, H(6´), J = 8.0 Hz; J = 0.8 Hz); 7.36 (t, 1 H,
3ꢀMeOC6H4, H(5´), J = 8.0 Hz); 7.93 (d, 1 H, CH=CHCO, J =
15.9 Hz). 13C NMR (CDCl3), δ: 55.1 (OMe); 116.4 (q, CF3, J =
291.5 Hz); 116.6 (CH=CHCO); 113.8, 118.1, 121.8, 130.1,
134.5, 160.0 (3ꢀMeOC6H4); 150.0 (CH=CHCO); 179.8 (q,
C=O, J = 36.6 Hz).
1,1,1ꢀTrifluoroꢀ4ꢀ(2,5ꢀdimethoxyphenyl)butꢀ3ꢀenꢀ2ꢀone
(1g). The yield was 69%, m.p. 42—43 °C. Found (%): C, 57.13;
H, 4.77. C12H11F3O2. Calculated (%): C, 56.94; H, 4.78. IR,
ν/cm–1: 1710 (C=O); 1615 (C=C). 1H NMR (CDCl3), δ:
3.81 and 3.88 (both s, 3 H each, OMe); 6.88 (d, 1 H,
2,5ꢀ(MeO)2C6H3, H(3´), J = 9.0 Hz); 7.02 (dd, 1 H,
2,5ꢀ(MeO)2C6H3, H(4´), J = 9.0 Hz; J = 3.0 Hz); 7.09 (d, 1 H,
2,5ꢀ(MeO)2C6H3, H(6´), J = 3.0 Hz); 7.10 (d, 1 H, CH=CHCO,
J = 16.2 Hz); 8.25 (d, 1 H, CH=CHCO, J = 16.2 Hz). 13C NMR
(CDCl3), δ: 55.7 (OMe); 55.9 (OMe); 112.5 (CH=CHCO);
116.5 (q, CF3, J = 290.5 Hz); 113.8, 116.9, 119.7, 122.6, 153.5,
154.1 (2,5ꢀ(MeO)2C6H3); 145.4 (CH=CHCO); 180.2 (q, C=O,
J = 34.9 Hz).
1,1,1ꢀTrifluoroꢀ4ꢀ(4ꢀmethylphenyl)butꢀ3ꢀenꢀ2ꢀone (1d).*
The yield was 42%, m.p. 35 °C. Found (%): C, 63.02; H, 5.11.
C12H11F3O. Calculated (%): C, 63.16; H, 4.86. IR, ν/cm–1
1730 (C=O); 1620 (C=C). H NMR (CDCl3), δ: 2.40 (s, 3 H,
Me); 6.96 (d, 1 H, CH=CHCO, J = 15.9 Hz); 7.26 (d, 2 H,
:
1
* Hereinafter, the atoms of the aryl substituents are primed.

Reaction of α,βꢀunsaturated CF3 ketones
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 2, February, 2004
439
The remaining unsaturated ketones were prepared accordꢀ
ing to known procedures.6—8
C, 64.57; H, 5.77. IR, ν/cm–1: 1710 (C=O); 3320 (O—H).
1H NMR (CDCl3, 600 MHz), δ: 1.60—1.68 (m, 1 H, Hax(7));
1.96—2.05 (m, 1 H, Hax(8)); 2.07—2.22 (m, 3 H, H(5), Hax(6),
Heq(6)); 2.15 (d, 1 H, Hax(3), J = 15.6 Hz); 2.24—2.29 (dm,
1 H, Heq(7)); 2.35 (br.d, 1 H, Heq(8), J = 14.6 Hz); 2.66 (dd,
1 H, H(1), J = 6.4 Hz, J = 1.9 Hz); 2.99 (br.s, 1 H, OH); 3.03
(dd, 1 H, Heq(3), J = 15.6 Hz, J = 9.3 Hz); 3.60 (d, 1 H, H(4),
J = 9.3 Hz); 7.16 (t, 1 H, C6H5, H(4´), J = 7.3 Hz); 7.29 (t,
2 H, C6H5, H(2´), H(6´), J = 7.3 Hz); 7.29 (t, 2 H, C6H5,
H(3´), H(5´), J = 7.3 Hz). 13C NMR (150 MHz, CDCl3), δ:
18.9 (C(7)); 30.6 (C(6)); 35.3 (C(4)); 37.6 (C(8)); 45.8 (C(3));
50.1 (C(1)); 52.5 (C(5)); 81.6 (q, C(2), J = 27.5 Hz); 125.0
(q, CF3, J = 279.6 Hz); 127.1, 128.2, 129.3, 147.2 (C6H5);
215.7 (C=O).
Reactions of trifluoromethyl ketones 1 with 1ꢀmorpholinoꢀ
cyclohexene (2b) (general procedure). Freshly distilled 1ꢀmorphoꢀ
linocyclohexene (2b) 9 (1.1 mmol) was added to a solution of
the corresponding α,βꢀunsaturated trifluoromethyl ketone 1
(1 mmol) in 95% EtOH (5 mL). The reaction mixture was
refluxed until the reaction was completed (TLC control, hexꢀ
ane—AcOEt, 3 : 1). Then a solution of NH4Cl (300 mg) in
water (5 mL) was added and the reaction mixture was kept at
≈20 °C for 3 h, diluted with water to ≈20 mL, and extracted with
CH2Cl2 (4×10 mL). The combined extracts were filtered through
a silica gel layer. The solvent was evaporated and the residue was
recrystallized from a 3 : 1 hexane—AcOEt mixture.
Single crystals of compound 3c were prepared by recrystalliꢀ
zation from 96% EtOH. Xꢀray diffraction study was carried out
on an EnrafꢀNonius CADꢀ4 diffractometer (β filter, MoꢀKα
radiation, λ = 0.71073 Å) at 293 K using the θ/2θ scanning
technique. The principal details of Xꢀray diffraction study and
crystallographic data for compound 3c are given in Table 2. The
structure was solved by direct methods. The positions of the
nonhydrogen atoms were refined by the fullꢀmatrix leastꢀsquares
method with anisotropic thermal parameters. The hydrogen atꢀ
oms were refined isotropically. Calculations were carried out
using the SHELXTL PLUS program package.
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(4ꢀmethylphenyl)ꢀ2ꢀtrifluoroꢀ
methylbicyclo[3.3.1]nonanꢀ9ꢀone (3d). The yield was 83%, m.p.
168 °C. Found (%): C, 65.37; H, 5.99. C17H19F3O2. Calcuꢀ
lated (%): C, 65.37; H, 6.13. IR, ν/cm–1: 1710 (C=O); 3320
(O—H). 1H NMR (CDCl3), δ: 1.60—1.68 (m, 1 H, Hax(7));
1.96—2.07 (m, 1 H, Hax(8)); 2.07—2.31 (m, 4 H, H(5), Hax(6),
Heq(6), Heq(7)); 2.13 (d, 1 H, Hax(3), J = 13.8 Hz); 2.28 (s, Me);
2.31—2.38 (m, 1 H, Heq(8)); 2.70—2.74 (m, 1 H, H(1)); 2.98
(br.s, OH); 3.02 (dd, 1 H, Heq(3), J =15.4 Hz, J = 9.1 Hz); 3.57
(d, 1 H, H(4), J = 9.1 Hz); 7.06 (d, 2 H, 4ꢀMeC6H4, H(3´),
H(5´), J = 8.2 Hz); 7.17 (d, 2 H, 4ꢀMeC6H4, H(2´), H(6´), J =
8.2 Hz). 13C NMR (DMSOꢀd6), δ: 18.4 (C(7)); 20.5 (Me); 30.3
(C(6)); 33.4 (C(4)); 37.0 (C(8)); 44.8 (C(3)); 50.7 (C(1)); 51.9
(C(5)); 79.3 (q, C(2), J = 26.3 Hz); 126.2 (CF3, J = 288.4 Hz);
127.5, 128.4, 134.4, 144.4 (4ꢀMeC6H4); 214.7 (C=O).
In the crystal structure, the molecules are linked in chains
by intermolecular O—H...O=C hydrogen bonds (dO—H
=
0.896 Å, dH...O = 1.95 Å, the O—H—O angle is 167.5°). The
molecule whose carbonyl group is involved in the hydrogen
bond is related to the molecule whose hydroxy group is involved
in this bond by the transformation (2 – x, y – 1/2, 3/2 – z).
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀphenylꢀ2ꢀtrifluoromethylbiꢀ
cyclo[3.3.1]nonanꢀ9ꢀone (3c). The yield was 95%, m.p. 184 °C.
Found (%): C, 64.42; H, 5.74. C16H17F3O2. Calculated (%):
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(3ꢀmethylphenyl)ꢀ2ꢀtrifluoroꢀ
methylbicyclo[3.3.1]nonanꢀ9ꢀone (3e). The yield was 98%, m.p.
163 °C. Found (%): C, 65.69; H, 6.41. C17H19F3O2. Calcuꢀ
lated (%): C, 65.37; H, 6.13. IR, ν/cm–1: 1710 (C=O); 3370
1
(O—H). H NMR (DMSOꢀd6), δ 1.48—1.58 (m, 1 H, Hax(7));
1.78—2.28 (m, 1 H, Hax(8)); 2.07—2.31 (m, 3 H, Hax(6), Heq(6),
Heq(7)); 2.16 (d, 1 H, Hax(3), J = 14.3 Hz); 2.21—2.29 (m, 1 H,
Table 2. Principal details of Xꢀray diffraction study and crystalꢀ
lographic data for compound 3c
Heq(8)); 2.23 (s, 3 H, Me); 2.58 (br.s, 1 H, H(5)); 2.62 (br.s,
1 H, H(1)); 2.83 (dd, 1 H, Heq(3), J = 15.4 Hz, J = 9.6 Hz); 3.59
(d, 1 H, H(4), J = 9.6 Hz); 6.02 (br.s, 1 H, OH); 6.93 (d, 1 H,
3ꢀMeC6H4, H(2´), J = 7.2 Hz); 7.02—7.14 (m, 3 H, 3ꢀMeC6H4,
H(4´), H(5´), H(6´)). 13C NMR (DMSOꢀd6), δ: 18.4 (C(7));
21.1 (Me); 30.5 (C(6)); 33.3 (C(4)); 37.1 (C(8)); 45.1 (C(3));
50.6 (C(1)); 51.9 (C(5)); 78.9 (q, C(2), J = 26.4 Hz); 124.7,
126.2, 127.7, 128.4, 136.6, 147.3 (3ꢀMeC6H4); 125.5 (q, CF3,
J = 288.4 Hz); 214.7 (C=O).
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(3ꢀmethoxyphenyl)ꢀ2ꢀtrifluoroꢀ
methylbicyclo[3.3.1]nonanꢀ9ꢀone (3f). The yield was 92%, m.p.
125 °C. Found (%): C, 62.17; H, 5.81. C17H19F3O3. Calcuꢀ
lated (%): C, 62.19; H, 5.83. IR, ν/cm–1: 1715 (C=O); 3325
(O—H). 1H NMR (DMSOꢀd6), δ: 1.48—1.59 (m, 1 H, Hax(7));
1.71—1.92 (m, 1 H, Hax(8)); 1.93—2.10 (m, 3 H, H(5), Hax(6),
Parameter
Characteristic
Molecular formula
Molecular weight
C16H17F3O2
298.30
Crystal system
Space group
Monoclinic
P21/c
a/Å
b/Å
c/Å
α/deg
9.954(2)
11.259(2)
12.742(3)
90
β/deg
98.60(3)
90
1412.0(5)
4
1.403
0.117
γ/deg
V/Å3
Heq(6)); 1.98 (d, 1 H, Hax(3), J = 15.0 Hz); 2.17 (d, 1 H, Heq(7),
Z
J = 14.4 Hz); 2.24 (br.d, 1 H, Heq(8), J = 12.0 Hz); 2.60 (d, 1 H,
H(1), J = 12.0 Hz); 2.83 (dd, 1 H, Heq(3), J = 15.0 Hz, J =
9.6 Hz); 3.59 (d, 1 H, H(4), J = 9.6 Hz); 3.69 (s, 3 H, OCH3);
6.04 (br.s, 1 H, OH); 6.70 (d, 1 H, 3ꢀMeOC6H4, H(2´), J =
7.5 Hz); 6.82 (d, 1 H, 3ꢀMeOC6H4, H(6´), J = 7.2 Hz); 6.90 (d,
1 H, 3ꢀMeOC6H4, H(4´), J = 7.9 Hz); 7.13 (t, 1 H, 3ꢀMeOC6H4,
H(5´), J = 7.9 Hz). 13C NMR (DMSOꢀd6), δ: 18.4 (C(7)); 30.3
(C(6)); 33.2 (C(4)); 37.0 (C(8)); 45.1 (C(3)); 50.7 (C(1)); 52.0
(C(5)); 54.8 (OMe); 78.9 (q, C(2), J = 26.3 Hz); 110.8, 113.8,
d/g cm–3
µ/mm–1
Scan range
2.07° < θ < 24.97°
2466
Number of independent reflections
Number of reflections with I > 2σ(I )
Number of parameters in refinement
R1 (I = 2σ(I ))
1749
259
0.0285
wR2 (based on all reflections)
0.0886

440
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 2, February, 2004
Nenajdenko et al.
120.0, 128.8, 148.9, 158.9 (3ꢀMeOC6H4); 125.5 (q, CF3, J =
288.4 Hz); 214.6 (C=O).
H(2´), H(6´), J = 7.3 Hz); 7.44 (t, 2 H, C6H5, H(3´), H(5´), J =
7.3 Hz). 13C NMR (CDCl3), δ: 18.6 (C(6)); 23.4 (C(7)); 30.1
(C(4)); 46.1 (C(3)); 47.8 (C(5)); 48.6 (C(1)); 81.1 (q, C(2), J =
29.0 Hz); 124.6 (q, CF3, J = 285.4 Hz); 126.4, 127.4, 128.9,
143.2 (C6H5); 212.7 (C=O).
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(4ꢀmethylphenyl)ꢀ2ꢀtrifluoroꢀ
methylbicyclo[3.2.1]octanꢀ8ꢀone (5d). The yield was 82%, m.p.
180 °C. Found (%): C, 64.61; H, 5.71. C16H17F3O2. Calcuꢀ
lated (%): C, 64.42; H, 5.74. IR, ν/cm–1: 1720 (C=O); 3320
(O—H). 1H NMR (CDCl3), δ: 1.84—1.98 (m, 2 H, Hax(6),
Hax(7)); 2.04 (br.s, 1 H, OH); 2.07—2.30 (m, 2 H, Heq(6),
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(2,5ꢀdimethoxyphenyl)ꢀ2ꢀtrifluoroꢀ
methylbicyclo[3.3.1]nonanꢀ9ꢀone (3g). The yield was 99%, m.p.
190 °C. Found (%): C, 60.37; H, 5.99. C18H21F3O4. Calcuꢀ
lated (%): C, 60.33; H, 5.91. IR, ν/cm–1: 1705 (C=O); 3370
(O—H). 1H NMR (DMSOꢀd6), δ: 1.47—1.58 (m, 1 H, Hax(7));
1.78—1.90 (m, 1 H, Hax(8)); 1.90—2.12 (m, 2 H, Hax(6),
H
eq(6)); 1.94 (d, 1 H, Hax(3), J = 15.0 Hz); 2.16 (d, 1 H, Heq(7),
J = 15.0 Hz); 2.23 (br.d, 1 H, Heq(8), J = 12.0 Hz); 2.57 (br.s,
2 H, H(1), H(5)); 2.72 (dd, 1 H, Heq(3), J = 15.0 Hz, J =
9.6 Hz); 3.63 (s, 3 H, C(5´)OCH3); 3.74 (s, 3 H, C(2´)OCH3);
3.82 (d, 1 H, H(4), J = 9.6 Hz); 5.97 (br.s, 1 H, OH); 6.68 (dd,
1 H, 2,5ꢀ(MeO)2C6H3, H(4´), J = 8.6 Hz, J = 2.8 Hz); 6.82 (d,
1 H, 2,5ꢀ(MeO)2C6H3, H(3´), J = 8.6 Hz); 6.85 (d, 1 H,
2,5ꢀ(MeO)2C6H3, H(6´), J = 2.8 Hz). 13C NMR (DMSOꢀd6),
δ: 18.4 (C(7)); 30.3 (C(6)); 31.5 (C(4)); 37.1 (C(8)); 38.2 (C(3));
50.2 (C(1)); 52.0 (C(5)); 55.1 (OMe); 55.7 (OMe); 79.4 (q,
C(2), J = 26.4 Hz); 110.4, 110.7; 115.3, 136.0, 149.8, 152.6
(2,5ꢀ(MeO)2C6H3); 125.4 (q, CF3, J = 288.3 Hz); 215.2 (C=O).
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀtrifluoromethylbiꢀ
cyclo[3.3.1]nonanꢀ9ꢀone (3h). The yield was 87%, m.p. 128 °C.
Found (%): C, 55.31; H, 4.84. C14H15F3O2S. Calculated (%):
C, 55.25, H, 4.97. IR, ν/cm–1: 1710 (C=O); 3325 (O—H).
1H NMR (DMSOꢀd6), δ: 1.48—1.57 (m, 1 H, Hax(7));
1.78—2.21 (m, 4 H, Hax(6), Heq(6), Heq(7), Hax(8)); 2.11 (d,
1 H, Hax(3), J = 15.4 Hz); 2.26 (br.d, 1 H, Heq(8), J = 15.8 Hz);
2.59 (br.s, 1 H, H(5)); 2.69 (br.s, 1 H, H(1)); 2.86 (dd, 1 H,
Heq(3), J = 15.4 Hz, J = 8.9 Hz); 3.90 (d, 1 H, H(4), J =
8.9 Hz); 6.06 (br.s, 1 H, OH); 6.85 (t, 1 H, 2ꢀC4H3S, H(4´), J =
3.2 Hz); 6.88 (d, 1 H, 2ꢀC4H3S, H(5´), J = 3.2 Hz); 7.26 (d,
1 H, 2ꢀC4H3S, H(3´), J = 4.8 Hz). 13C NMR (DMSOꢀd6), δ:
18.4 (C(7)); 30.2 (C(6)); 33.5 (C(4)); 36.1 (C(8)); 40.7 (C(3));
51.7 (C(1)); 52.1 (C(5)); 78.8 (q, C(2), J = 26.4 Hz); 123.4,
124.4, 126.4, 149.8 (2ꢀC4H3S); 125.4 (q, CF3, J = 288.4 Hz);
213.2 (C=O).
Reactions of trifluoromethyl ketones 1 with 1ꢀmorpholinoꢀ
cyclopentene (2a) and 1ꢀmethylꢀ4ꢀmorpholinoꢀ1,2,5,6ꢀtetraꢀ
hydropyridine (2c) (general procedure). Freshly distilled enamꢀ
ine 2a or 2c (1.1 mmol) was added to a solution of the correꢀ
sponding α,βꢀunsaturated trifluoromethyl ketone 1 (1 mmol)
in 96% EtOH (5 mL) and the reaction mixture was kept at
≈20 °C until the reaction was completed (TLC control, a hexꢀ
ane—AcOEt mixture, 3 : 1). Then a solution of NH4Cl (300 mg)
in water (5 mL) was added and the reaction mixture was kept at
≈20 °C for 3 h, diluted with water to ≈20 mL, and extracted with
CH2Cl2 (4×10 mL). The combined extracts were filtered through
a silica gel layer. The solution was concentrated and the resiꢀ
due was recrystallized from a 3 : 1 hexane—AcOEt mixture.
Enaminoketone 4 was prepared from ketones 1a and 1b. Its
characteristics are identical to those published in the literature.10
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀphenylꢀ2ꢀtrifluoromethylbiꢀ
cyclo[3.2.1]octanꢀ8ꢀone (5c). The yield was 99%, m.p. 175 °C.
Found (%): C, 63.47; H, 5.03. C15H15F3O2. Calculated (%):
C, 63.38; H, 5.32. IR, ν/cm–1: 1735 (C=O); 3320 (O—H).
1H NMR (CDCl3), δ: 1.81—2.03 (m, 2 H, Hax(6), Hax(7));
2.07—2.30 (m, 3 H, Heq(6), Heq(7), OH); 2.19 (d, 1 H, Hax(3),
J = 15.0 Hz); 2.41—2.65 (d, 1 H, H(5), J = 6.7 Hz); 2.69 (dd,
1 H, Heq(3), J = 15.0 Hz, J = 8.2 Hz); 2.78, 2.92 (dm, 1 H,
H(1), J = 4.4 Hz); 3.48 (dd, 1 H, H(4), J = 8.2 Hz, J = 1.5 Hz);
7.18 (t, 1 H, C6H5, H(4´), J = 7.3 Hz); 7.28 (t, 2 H, C6H5,
Heq(7)); 2.17 (d, 1 H, Hax(3), J = 15.2 Hz); 2.29 (s, 3 H, Me);
2.42—2.58 (dm, 1 H, H(5), J = 6.7 Hz); 2.67 (dd, 1 H, Heq(3),
J = 15.2 Hz, J = 8.0 Hz); 2.78—2.93 (dm, 1 H, H(1), J =
7.9 Hz); 3.46 (dd, 1 H, H(4), J = 8.0 Hz, J = 1.2 Hz); 7.09 (d,
2 H, 4ꢀMeC6H4, H(2´), H(6´), J = 8.0 Hz); 7.33 (d, 2 H,
4ꢀMeC6H4, H(3´), H(5´), J = 8.0 Hz). 13C NMR (CDCl3), δ:
18.6 (C(6)); 20.9 (Me); 23.4 (C(7)); 30.2 (C(4)); 46.1 (C(3));
47.5 (C(5)); 48.7 (C(1)); 81.2 (q, C(2), J = 29.0 Hz); 124.6 (q,
CF3, J = 286.9 Hz); 127.3, 129.1, 136.0 140.0 (4ꢀMeC6H4);
212.6 (C=O).
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(3ꢀmethylphenyl)ꢀ2ꢀtrifluoroꢀ
methylbicyclo[3.2.1]octanꢀ8ꢀone (5e). The yield was 94%, m.p.
121—122 °C. Found (%): C, 64.41; H, 5.77. C16H17F3O2. Calꢀ
culated (%): C, 64.42; H, 5.74. IR, ν/cm–1: 1740 (C=O); 3380
(O—H). 1H NMR (CDCl3), δ: 1.83—2.02 (m, 2 H, Hax(6),
H
ax(7)); 2.07 (br.s, 1 H, OH); 2.13—2.25 (m, 2 H Heq(6),
Heq(7)); 2.19 (d, 1 H, Hax(3), J = 15.0 Hz); 2.32 (s, Me);
2.43—2.60 (dm, 1 H, H(5), J = 6.7 Hz); 2.68 (dd, 1 H, Heq(3),
J = 15.0 Hz, J = 8.5 Hz); 2.77—2.86 (dm, 1 H, H(1), J =
4.7 Hz); 3.70 (dd, 1 H, H(4), J = 8.5 Hz, J = 2.0 Hz); 7.00 (t,
1 H, 3ꢀMeC6H4, H(2´), J = 7.3 Hz); 7.18 (t, 1 H, 3ꢀMeC6H4,
H(4´), J = 7.3 Hz); 7.23—7.29 (m, 2 H, 3ꢀMeC6H4, H(5´),
H(6´)). 13C NMR (CDCl3), δ: 18.6 (C(8)); 21.5 (Me); 23.4
(C(7)); 30.3 (C(4)); 46.0 (C(3)); 47.7 (C(5)); 48.6 (C(1)); 81.2
(q, C(2), J = 29.0 Hz); 124.4, 127.2, 128.3, 128.4, 138.0, 143.1
(3ꢀMeC6H4); 124.5 (q, CF3, J = 285.4 Hz); 212.5 (C=O).
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(3ꢀmethoxyphenyl)ꢀ2ꢀtrifluoroꢀ
methylbicyclo[3.2.1]octanꢀ8ꢀone (5f). The yield was 88%, m.p.
98 °C. Found (%): C, 61.49; H, 5.19. C16H17F3O3. Calcuꢀ
lated (%): C, 61.14; H, 5.45. IR, ν/cm–1: 1735 (C=O); 3370
(O—H). 1H NMR (CDCl3), δ: 1.83—2.02 (m, 2 H, Hax(6),
Hax(7)); 2.11—2.23 (m, 2 H Heq(6), Heq(7)); 2.19 (d, 1 H,
Hax(3), J = 15.0 Hz); 2.28 (br.s, 1 H, OH); 2.43—2.58 (dm, 1 H,
H(5), J = 7.0 Hz); 2.67 (dd, 1 H, Heq(3), J = 15.0 Hz, J =
8.5 Hz); 2.77—2.93 (dm, 1 H, H(1), J = 4.7 Hz); 3.45 (dd, 1 H,
H(4), J = 8.2 Hz, J = 2.0 Hz); 3.77 (s, 3 H, OMe); 6.73 (dd, 1 H,
3ꢀMeOC6H4, H(2´), J = 8.2 Hz, J = 2.0 Hz); 6.76—6.84 (m,
1 H, 3ꢀMeOC6H4, H(4´), J = 2.0 Hz); 6.97—7.07 (m, 1 H,
3ꢀMeOC6H4, H(6´)); 7.19 (t, 1 H, 3ꢀMeOC6H4, H(5´), J =
7.9 Hz). 13C NMR (CDCl3), δ: 18.6 (C(6)); 23.4 (C(7)); 30.1
(C(4)); 46.2 (C(3)); 47.9 (C(5)); 48.6 (C(1)); 55.1 (OMe); 81.2
(q, C(2), J = 29.0 Hz); 111.9, 113.4, 119.8, 129.3, 144.8, 159.5
(3ꢀMeOC6H4); 125.2 (q, CF3, J = 285.4 Hz); 212.7 (C=O).
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(2,5ꢀdimethoxyphenyl)ꢀ2ꢀtrifluoroꢀ
methylbicyclo[3.2.1]octanꢀ8ꢀone (5g). The yield was 87%, m.p.
145 °C. Found (%): C, 59.75; H, 5.60. C17H19F3O4. Calcuꢀ
lated (%): C, 59.30; H, 5.56. IR, ν/cm–1: 1740 (C=O); 3390
(O—H). 1H NMR (CDCl3), δ: 1.85—2.02 (m, 2 H, Hax(6),
Hax(7)); 2.05—2.26 (m, 3 H, Heq(6), Heq(7), OH); 2.13 (d, 1 H,
Hax(3), J = 15.8 Hz); 2.47—2.60 (dm, 1 H, H(5), J = 7.0 Hz);

Reaction of α,βꢀunsaturated CF3 ketones
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 2, February, 2004
441
2.58 (dd, 1 H, Heq(3), J = 15.8 Hz, J = 8.8 Hz); 2.63—2.70 (dm,
1 H, H(1), J = 5.0 Hz); 3.70 (dd, 1 H, H(4), J = 8.8 Hz,
J =2.0 Hz); 3.74 (s, 3 H, OMe); 3.78 (s, 3 H, OMe); 6.73 (d,
1 H, 2,5ꢀ(MeO)2C6H3, H(3´), J = 2.6 Hz); 6.75—6.79 (m, 1 H,
2,5ꢀ(MeO)2C6H3, H(6´)); 7.36 (d, 1 H, 2,5ꢀ(MeO)2C6H3,
H(4´), J = 2.6 Hz). 13C NMR (CDCl3), δ: 18.6 (C(6)); 23.7
(C(7)); 28.3 (C(4)); 42.4 (C(3)); 46.2 (C(5)); 48.4 (C(1)); 55.6
(OMe); 55.7 (OMe); 81.2 (q, C(2), J = 27.5 Hz); 110.7, 112.7,
115.0, 132.7, 150.2, 153.9 (2,5ꢀ(MeO)2C6H3); 124.4 (q, CF3,
J = 285.4 Hz); 213.7 (C=O).
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀtrifluoromethylbiꢀ
cyclo[3.2.1]octanꢀ8ꢀone (5h). The yield was 99%, m.p. 105 °C.
Found (%): C, 53.94; H, 4.41. C13H13F3O2S. Calculated (%):
C, 53.78; H, 4.51. IR, ν/cm–1: 1730 (C=O); 3310 (O—H).
1H NMR (CDCl3), δ: 1.80—2.03 (m, 2 H, Hax(6), Hax(7));
2.13—2.24 (m, 2 H Heq(6), Heq(7)); 2.27 (d, 1 H, Hax(3), J =
15.2 Hz); 2.34 (br.s, 1 H, OH); 2.46—2.61 (dm, 1 H, H(1), J =
6.7 Hz); 2.64 (dd, 1 H, Heq(3), J = 15.2 Hz, J = 7.6 Hz);
2.79—2.92 (dm, 1 H, H(5), J = 6.7 Hz); 3.68 (dd, 1 H, H(4), J =
7.6 Hz, J = 2.6 Hz); 6.89 (dd, 1 H, 2ꢀC4H3S, H(4´), J = 5.0 Hz,
J = 3.5 Hz); 7.10 (dt, 1 H, 2ꢀC4H3S, H(3´), J = 3.5 Hz, J =
1.2 Hz); 7.15 (dd, 1 H, 2ꢀC4H3S, H(5´), J = 5.0 Hz, J = 1.2 Hz).
13C NMR (CDCl3), δ: 18.6 (C(6)); 22.7 (C(7)); 30.4 (C(4));
43.8 (C(3)); 47.3 (C(5)); 49.0 (C(1)); 81.2 (q, C(2), J = 29.0 Hz);
124.5 (q, CF3, J = 285.4 Hz); 123.9, 125.1, 127.0, 145.8
(2ꢀC4H3S); 211.5 (C=O).
209 °C. Found (%): C, 62.51; H, 6.31. C17H20F3NO2. Calcuꢀ
lated (%): C, 62.38; H, 6.16. IR, ν/cm–1: 1730 (C=O); 3410
(O—H). 1H NMR (CDCl3), δ: 1.73 (br.s, 1 H, OH); 2.04 (d,
1 H, Hax(7), J = 14.3 Hz); 2.28 (br.s, 6 H, 4ꢀCH3C6H4, MeN);
2.45 (dd, 1 H, Hax(4), J = 12.0 Hz, J = 1.5 Hz); 2.64 (dd, 1 H,
Hax(2), J = 11.0 Hz, J = 2.6 Hz); 2.61—2.75 (dm, 1 H, H(1), J =
2.6 Hz); 2.91 (br.s, 1 H, H(5)); 3.24 (dt, 1 H, Heq(2), J =
11.0 Hz, J = 2.6 Hz); 3.29 (d, 1 H, Heq(4), J = 12.0 Hz); 3.70 (d,
1 H, H(8), J = 8.5 Hz); 3.81 (dd, 1 H, Heq(7), J = 14.3 Hz, J =
8.5 Hz); 7.07 (d, 2 H, 4ꢀCH3C6H4, H(2´), H(6´), J = 8.0 Hz);
7.17 (d, 2 H, 4ꢀCH3C6H4, H(3´), H(5´), J = 8.0 Hz). 13C NMR
(CDCl3), δ: 20.8 (4ꢀCH3C6H4); 35.9 (C(8)); 44.3 (C(7)); 45.5
(NMe); 51.0 (C(1)); 52.7 (C(5)); 58.1 (C(2)); 65.0 (C(4)); 80.3
(q, C(6), J = 29.0 Hz); 127.3, 129.2, 135.9, 142.8 (4ꢀCH3C6H4);
124.6 (q, CF3, J = 286.9 Hz); 212.8 (C=O).
6ꢀHydroxyꢀ8ꢀ(3ꢀmethoxyphenyl)ꢀ3ꢀmethylꢀ6ꢀtrifluoroꢀ
methylꢀ3ꢀazabicyclo[3.3.1]nonanꢀ9ꢀone (6e). The yield was 79%,
m.p. 119 °C. Found (%): C, 59.31; H, 5.81. C17H20F3NO3.
Calculated (%): C, 59.47; H, 5.87. IR, ν/cm–1: 1720 (C=O);
1
3400 (O—H). H NMR (CDCl3), δ: 1.85 (br.s, 1 H, OH); 2.06
(d, 1 H, Hax(7), J = 14.4 Hz); 2.28 (s, 3 H, MeN); 2.45 (dd, 1 H,
Hax(4), J = 12.3 Hz, J = 1.8 Hz); 2.64 (dd, 1 H, Hax(2), J =
11.0 Hz, J = 2.6 Hz); 2.58—2.73 (dm, 1 H, H(1), J = 2.6 Hz);
2.77—2.95 (dm, 1 H, H(5), J = 1.8 Hz); 3.23 (dt, 1 H, Heq(2),
J = 11.0 Hz, J = 2.6 Hz); 3.29 (d, 1 H, Heq(4), J = 12.3 Hz);
3.70 (d, 1 H, H(8), J = 8.8 Hz); 3.76 (s, 3 H, MeO); 3.81 (dd,
1 H, Heq(7), J = 14.4 Hz, J = 8.8 Hz); 6.71 (dd, 1 H,
3ꢀMeOC6H4, H(2´), J = 7.3 Hz, J = 2.3 Hz); 6.87 (d, 2 H,
3ꢀMeOC6H4, H(4´), H(5´), J = 7.3 Hz); 7.17 (t, 1 H,
3ꢀMeOC6H4, H(6´), J = 7.6 Hz). 13C NMR (CDCl3), δ: 35.8
(C(8)); 44.4 (C(7)); 45.9 (NMe); 51.0 (C(1)); 52.7 (C(5)); 55.1
(OMe); 58.1 (C(2)); 65.3 (C(4)); 80.2 (q, C(6), J = 29.0 Hz);
112.5, 113.9, 120.4, 130.3, 148.3, 160.5 (3ꢀMeOC6H4); 126.2
(q, CF3, J = 285.4 Hz); 212.6 (C=O).
(2R*,4S*)ꢀ2ꢀHydroxyꢀ4ꢀ(3ꢀindolyl)ꢀ2ꢀtrifluoromethylbiꢀ
cyclo[3.2.1]octanꢀ8ꢀone (5i). The yield was 52%, m.p. 168 °C.
Found (%): C, 63.07; H, 4.88. C17H16F3NO2. Calculated (%):
C, 63.15; H, 4.99. IR, ν/cm–1: 1730 (C=O); 3260 (N—H); 3410
(O—H). 1H NMR (CDCl3), δ: 1.89—2.05 (m, 2 H, Hax(6),
H
ax(7)); 2.12—2.25 (m, 2 H, Heq(6), Heq(7)); 2.27 (br.s, 1 H,
OH); 2.29 (d, 1 H, Hax(3), J = 15.0 Hz); 2.48—2.64 (d, 1 H,
H(1), J = 6.5 Hz); 2.68 (dd, 1 H, Heq(3), J = 15.0 Hz, J =
7.6 Hz); 2.76—2.89 (dm, 1 H, H(5), J = 6.2 Hz); 3.74 (d, 1 H,
H(4), J = 7.6 Hz); 7.12 (t, 1 H, 3ꢀC8H6N, H(5´), J = 7.6 Hz);
7.19 (t, 1 H, 3ꢀC8H6N, H(6´), J = 7.6 Hz); 7.34 (d, 1 H,
3ꢀC8H6N, H(7´), J = 7.9 Hz); 7.38 (br.s, 1 H, 3ꢀC8H6N, H(2´));
7.49 (d, 1 H, 3ꢀC8H6N, H(4´), J = 7.6 Hz); 8.10 (br.s, 1 H,
NH). 13C NMR (CDCl3), δ: 18.8 (C(6)); 23.2 (C(7)); 28.6
(C(4)); 40.1 (C(3)); 47.2 (C(5)); 49.0 (C(1)); 81.6 (q, C(2), J =
29.0 Hz); 111.5, 118.1, 119.6, 122.3, 122.8, 123.5, 126.2, 135.9
(3ꢀC8H6N); 124.5 (q, CF3, J = 285.4 Hz); 213.7 (C=O).
6ꢀHydroxyꢀ3ꢀmethylꢀ8ꢀphenylꢀ6ꢀtrifluoromethylꢀ3ꢀazabiꢀ
cyclo[3.3.1]nonanꢀ9ꢀone (6c). The yield was 70%, m.p. 148 °C.
Found (%): C, 61.15; H, 5.87. C16H18F3NO2. Calculated (%):
C, 61.33; H 5.79. IR, ν/cm–1: (C=O) 1715; 3370 (O—H).
1H NMR (CDCl3), δ: 2.06 (d, 1 H, Hax(7) J = 14.1 Hz); 2.24
(br.s, 1 H, OH); 2.29 (s, 3 H, MeN); 2.46 (dd, 1 H, Hax(4), J =
12.1 Hz, J = 1.8 Hz); 2.65 (dd, 1 H, Hax(2), J = 11.0 Hz, J =
2.6 Hz); 2.58—2.70 (dm, 1 H, H(1), J = 2.6 Hz); 2.87—2.98 (dm,
1 H, H(5), J = 1.8 Hz); 3.25 (dt, 1 H, Heq(2), J = 11.0 Hz, J =
2.6 Hz); 3.30 (d, 1 H, Heq(4), J = 12.1 Hz); 3.73 (d, 1 H, H(8),
J = 8.8 Hz); 3.83 (dd, 1 H, Heq(7), J = 14.1 Hz, J = 8.8 Hz); 7.16
(t, 1 H, C6H5, H(4´), J = 7.0 Hz); 7.22—7.39 (m, 4 H, C6H5,
H(2´), H(3´), H(5´), H(6´)). 13C NMR (CDCl3), δ: 35.9 (C(8));
44.4 (C(7)); 45.9 (NMe); 50.9 (C(1)); 52.7 (C(5)); 58.1 (C(2));
65.0 (C(4)); 80.0 (q, C(6), J = 29.0 Hz); 124.8 (q, CF3, J =
285.4 Hz); 126.3, 127.5, 128.6, 145.8 (C6H5); 212.7 (C=O).
6ꢀHydroxyꢀ3ꢀmethylꢀ8ꢀ(4ꢀmethylphenyl)ꢀ6ꢀtrifluoromethylꢀ
3ꢀazabicyclo[3.3.1]nonanꢀ9ꢀone (6d). The yield was 61%, m.p.
8ꢀ(2,5ꢀDimethoxyphenyl)ꢀ6ꢀhydroxyꢀ3ꢀmethylꢀ6ꢀtrifluoroꢀ
methylꢀ3ꢀazabicyclo[3.3.1]nonanꢀ9ꢀone (6f). The yield was 50%,
m.p. 158 °C. Found (%): C, 57.74; H, 5.81. C18H22F3NO4.
Calculated (%): C, 57.90; H, 5.94. IR, ν/cm–1: 1720 (C=O);
1
3340 (O—H). H NMR (CDCl3), δ: 1.89 (br.s, 1 H, OH); 1.98
(d, 1 H, Hax(7), J = 15.0 Hz); 2.29 (s, 3 H, MeN); 2.45 (dd, 1 H,
Hax(4), J = 12.0 Hz, J = 1.8 Hz); 2.62 (dd, 1 H, Hax(2), J =
11.1 Hz, J = 2.6 Hz); 2.67 (br.s, 1 H, H(1)); 2.68—2.82 (dm,
1 H, H(5), J = 1.8 Hz); 3.25 (dt, 1 H, Heq(2), J = 11.1 Hz, J =
2.6 Hz); 3.29 (d, 1 H, Heq(4), J = 12.0 Hz); 3.65 (dd, 1 H,
Heq(7), J = 15.0 Hz, J = 9.1 Hz); 3.71 (s, 3 H, MeO); 3.80 (s,
3 H, MeO); 4.00 (d, 1 H, H(8), J = 9.1 Hz); 6.70 (dd, 1 H,
2,5ꢀ(MeO)2C6H3, H(2´), J = 8.8 Hz, J = 2.9 Hz); 6.75 (d,
1 H, 2,5ꢀ(MeO)2C6H3, H(4´), J = 8.8 Hz); 6.97 (d, 1 H,
2,5ꢀ(MeO)2C6H3, H(6´), J = 2.9 Hz). 13C NMR (CDCl3),
δ: 33.6 (C(8)); 39.8 (C(7)); 44.4 (NMe); 51.3 (C(1)); 52.8
(C(5)); 55.6 ((OMe)2); 58.1 (C(2)); 65.2 (C(4)); 80.3 (q, C(6),
J = 29.0 Hz); 110.9, 112.4, 114.1, 134.9, 149.9, 153.4
(2,5ꢀ(MeO)2C6H3); 124.8 (q, CF3, J = 285.4 Hz); 213.4 (C=O).
6ꢀHydroxyꢀ3ꢀmethylꢀ8ꢀ(2ꢀthienyl)ꢀ6ꢀtrifluoromethylꢀ3ꢀazaꢀ
bicyclo[3.3.1]nonanꢀ9ꢀone (6g). The yield was 66%, m.p. 141 °C.
Found (%): C, 52.79; H, 5.02. C14H16F3O2S. Calculated (%):
C, 52.65; H, 5.05. IR, ν/cm–1: 1720 (C=O); 3350 (O—H).
1H NMR (CDCl3), δ: 1.99 (br.s, 1 H, OH); 2.23 (d, 1 H, Hax(7),
J = 14.4 Hz); 2.27 (s, 3 H, MeN); 2.43 (dd, 1 H, Hax(4), J =
11.4 Hz, J = 1.5 Hz); 2.62 (dd, 1 H, Hax(2), J = 11.1 Hz, J =
2.6 Hz); 2.66 (br.s, 1 H, H(1)); 2.97 (br.s, 1 H, H(5)); 3.25 (dt,

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Nenajdenko et al.
1 H, Heq(2), J = 11.1 Hz, J = 2.6 Hz); 3.30 (d, 1 H, Heq(4), J =
11.4 Hz); 3.83 (dd, 1 H, Heq(7), J = 14.4 Hz, J = 8.2 Hz); 3.94
(d, 1 H, H(8), J = 8.2 Hz); 6.87 (dd, 1 H, 2ꢀC4H3S, H(4´), J =
5.0 Hz, J = 3.5 Hz); 6.94 (dt, 1 H, 2ꢀC4H3S, H(3´), J = 3.5 Hz,
J = 1.0 Hz); 7.12 (dd, 1 H, 2ꢀC4H3S, H(5´), J = 5.0 Hz, J =
1.0 Hz). 13C NMR (CDCl3), δ: 35.9 (C(8)); 41.7 (C(7)); 44.3
(NMe); 51.8 (C(1)); 53.1 (C(5)); 57.9 (C(2)); 64.0 (C(4)); 80.2
(q, C(6), J = 29.0 Hz); 123.7, 124.6, 127.2, 148.5 (2ꢀC4H3S);
125.5 (q, CF3, J = 286.9 Hz); 211.0 (C=O).
References
1. R. Filler, Organofluorine Chemicals and Their Industrial Appliꢀ
cations, Ed. R. E. Banks, Ellis Horwood, London, 1979, 123.
2. R. Filler, Biomedicinal Aspect of Fluorine Chemistry,
Ed. Y. Kobayashi, Kodansha & Elsevier Biomedical, Tokyo,
1982, 1.
3. V. G. Nenajdenko, A. V. Sanin, and E. S. Balenkova, Molꢀ
ecules, 1997, 2, 186.
6ꢀHydroxyꢀ8ꢀ(3ꢀindolyl)ꢀ3ꢀmethylꢀ6ꢀtrifluoromethylꢀ3ꢀazaꢀ
bicyclo[3.3.1]nonanꢀ9ꢀone (6h). The yield was 51%, m.p. 148 °C.
Found (%): C, 61.16; H, 5.34. C18H19F3NO2. Calculated (%):
C, 61.36; H, 5.44. IR, ν/cm–1: 1725 (C=O); 3410 (O—H).
1H NMR (CDCl3), δ: 2.03 (br.s, 1 H, OH); 2.27 (d, 1 H, Hax(7),
J = 14.4 Hz); 2.31 (s, 3 H, MeN); 2.45 (dd, 1 H, H(4), J =
12.1 Hz, J = 2.3 Hz); 2.67 (dd, 1 H, Hax(2), J = 11.4 Hz, J =
2.9 Hz); 2.71 (br.s, 1 H, H(1)); 2.92 (br.s, 1 H, H(5)); 3.31 (dd,
1 H, Heq(2), J = 12.0 Hz, J = 2.9 Hz); 3.33 (d, 1 H, Heq(4), J =
12.1 Hz); 3.81 (dd, 1 H, Heq(7), J = 14.4 Hz, J = 7.9 Hz); 4.00
(d, 1 H, H(8), J = 7.9 Hz); 7.13 (m, 2 H, 3ꢀC8H6N, H(2´),
H(5´), J = 7.6 Hz); 7.20 (t, 1 H, 3ꢀC8H6N, H(4´), J = 8.2 Hz);
7.34 (d, 1 H, 3ꢀC8H6N, H(6´), J = 7.9 Hz); 7.54 (d, 1 H,
3ꢀC8H6N, H(7´), J = 7.6 Hz); 8.23 (br.s, 1 H, NH). 13C NMR
(CDCl3), δ: 33.4 (C(8)); 37.8 (C(7)); 44.4 (NMe); 51.8 (C(1));
53.4 (C(5)); 58.0 (C(2)); 64.5 (C(4)); 80.6 (q, C(6), J = 29.0 Hz);
111.5, 118.2, 119.6, 119.8, 122.1, 122.3, 125.8, 136.0 (3ꢀC8H6N);
124.3 (q, CF3, J = 285.4 Hz); 213.3 (C=O).
4. V. G. Nenajdenko, A. V. Sanin, and E. S. Balenkova, Usp.
Khim., 1999, 68, 483 [Russ. Chem. Rev., 1999, 68, 437 (Engl.
Transl.)].
5. R. Andrew, J. Mellor, and G. Reid, Tetrahedron, 2000,
56, 7255.
6. A. V. Sanin, V. G. Nenajdenko, K. I. Smolko, D. I.
Denisenko, and E. S. Balenkova, Synthesis, 1998, 842.
7. A. V. Sanin, V. G. Nenajdenko, and E. S. Balenkova, Zh. Org.
Khim., 1998, 34, 842 [Russ. J. Org. Chem., 1998, 34 (Engl.
Transl.)].
8. M. G. Gorbunova, I. I. Gerus, and V. P. Kukhar, J. Fluorine
Chem., 1993, 65, 25.
9. G. Stork and H. K. Landesman, J. Am. Chem. Soc., 1956,
78, 5128.
10. A. L. Krasovskii, V. G. Nenajdenko, and E. S. Balenkova,
Izv. Akad. Nauk, Ser. Khim., 2001, 1329 [Russ. Chem. Bull.,
Int. Ed., 2001, 50, 1395].
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 04ꢀ03ꢀ
32285ꢀa).
Received July 15, 2003;
in revised form December 18, 2003