Synthesis of CF3-substituted 1,2,3,4-tetrahydroisoquinolines and 1,2,3,6-tetrahydropyridines

Article abstract of DOI:10.1007/s11172-010-0362-2

A three-step method for the preparation of CF₃-substituted 1,2,3,4-tetrahydroisoquino-lines and 1,2,3,6-tetrahydropyridines has been suggested. The first step includes alkylation of isoquinoline or 4-methylpyridine at the nitrogen atom with the

Full text of DOI:10.1007/s11172-010-0362-2

Russian Chemical Bulletin, International Edition, Vol. 59, No. 11, pp. 2102—2107, November, 2010
2102
Synthesis of CF3ꢀsubstituted 1,2,3,4ꢀtetrahydroisoquinolines
and 1,2,3,6ꢀtetrahydropyridines
I. Yu. Chernyshov, V. V. Levin, A. D. Dilman, P. A. Belyakov, M. I. Struchkova, and V. A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: dilman@ioc.ac.ru
A threeꢀstep method for the preparation of CF3ꢀsubstituted 1,2,3,4ꢀtetrahydroisoquinoꢀ
lines and 1,2,3,6ꢀtetrahydropyridines has been suggested. The first step includes alkylation of
isoquinoline or 4ꢀmethylpyridine at the nitrogen atom with the formation of salts, which are
involved into the reaction with Grignard reagent or lithium triethylborohydride to give enꢀ
amines. The enamines undergo nucleophilic trifluoromethylation upon the action of Me3SiCF3
under acidic conditions.
Key words: trifluoromethylation, amines, trimethyl(trifluoromethyl)silane.
Scheme 1
Amines containing trifluoromethyl group at the
Cα atom are an important class of biologically active comꢀ
pounds.1—4 The most efficient approaches to αꢀCF3ꢀsubꢀ
stituted amines include nucleophilic addition5 and
1,3ꢀproton shift6 reactions involving imines of trifluoroꢀ
acetic aldehyde, as well as addition reactions of trifluoroꢀ
methyl carbanion at the C=N bond of azomethine subꢀ
strates7,8 and iminium cations.9
Among different αꢀ(trifluoromethyl)amines, 3ꢀtriꢀ
fluoromethylꢀ1,2,3,4ꢀtetrahydroisoquinolines are of speꢀ
cial interest,4 since they are selective inhibitors of phenylꢀ
ethanolamineꢀNꢀmethyltransferase, the enzyme catalyzing
the last step of biosynthesis of adrenalin. The earlier4 deꢀ
scribed method for the synthesis of such compounds was
based on the use of ethyl trifluoroacetate as a source of
a CF3 group, that required performing six and more steps.
During preparation of this work, another approach has
been reported, which included oxidative trifluoromethylaꢀ
tion of 1,2,3,4ꢀtetrahydroisoquinolines.10
In the present work, we suggest more simple threeꢀstep
method for the synthesis of 3ꢀCF3ꢀsubstituted 1,2,3,4ꢀ
tetrahydroisoquinolines (Scheme 1). In the first step, isoꢀ
quinoline is alkylated at the nitrogen atom. Then, isoꢀ
quinolinium salt 1 is involved into the reaction with
nucleophile (Grignard reagent or hydride anion) with the
formation of enamine 2, which can give the trifluoroꢀ
methylation reaction with the formation of products 3.
The trifluoromethylation reaction of enamines, recentꢀ
ly developed in our group,11,12 is carried out with the
use of trimethyl(trifluoromethyl)silane upon the action
of hydrofluoric acid, generated in situ from potassium
hydrogen difluoride and trifluoromethanesulfonic acid11
(Scheme 2). The mechanism of the reaction includes proꢀ
tonation of enamine 2 with hydrofluoric acid with subseꢀ
quent reaction of the iminium cation with the siliconꢀ
containing reagent, which is activated by the hydrogen
difluoride anion.
The reaction of isoquinolinium salts 1 with Grignard
reagents was performed in THF at the temperatures from
–78 to 25 °C. Subsequent extraction with light petroleum
allowed us to isolate enamines 2 in the individual state as
light liquids. However, they are extremely sensitive to air
oxygen, that makes difficult their isolation and handling.
This was the reason that in some experiments enamines 2
were involved into the trifluoromethylation reaction withꢀ
out additional purification. The results obtained are given
in Table 1.
The trifluoromethylation reaction leads to a mixture of
isomers in approximately equal ratio even in the case of
isopropylꢀsubstituted enamines (see Table 1, entries 2
and 5). Relative configuration of 3a was established based
on the NOESY data for the transꢀisomer. Assignment for
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2048—2053, November, 2010.
1066ꢀ5285/10/5911ꢀ2102 © 2010 Springer Science+Business Media, Inc.

CF3ꢀSubstituted amines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 11, November, 2010 2103
Scheme 2
compounds 3c—e was made similarly based on the differꢀ
ences in the chemical shifts for the proton CHCF3 in
transꢀ and cisꢀisomers: for the transꢀisomers, this proton is
more downfield shifted (by ~0.4 ppm). The low stereoꢀ
selectivity can be attributed to the placement of substituꢀ
ent R2 in the pseudoequatorial position, that in the transiꢀ
tion state does not lead to the repulsive interactions with
the incoming CF3 carbanion. We made an attempt to obꢀ
tain an enamine containing a tertꢀbutyl group, however,
the reaction of salt 1a with tertꢀbutylmagnesium chloride
predominantly leads to the reduction of the iminium salt
and the yield of the target enamine does not exceed 10%
(Scheme 3).
pounds 6 and 7 and expected product 8 in trace amounts,
that was inferred from the 1H and 19F NMR spectra
(Scheme 4). The initial step of this reaction includes genꢀ
eration of iminium cation 9, which abstracts hydride anꢀ
ion from the starting enamine 4 with the formation of
compound 7 and 2ꢀmethylꢀ4ꢀphenylisoquinolinium catꢀ
ion, which reacts with the siliconꢀcontaining reagent giving
rise to enamine 6. To confirm the structure of enamine 6,
a sample of this compound was obtained by the reaction of
iminium salt 5 with Me3SiCF3 in the presence of potasꢀ
sium fluoride.13 At the same time, tetrahydroisoquinoline
7 was known earlier.14
It was also reasonable to apply the alkylation—nucleoꢀ
philic addition—trifluoromethylation sequence for the synꢀ
thesis of CF3ꢀsubstituted tetrahydropyridines. Thus, benꢀ
zylation of 4ꢀmethylpyridine gives salts 10a,b in quantitaꢀ
tive yield, which were involved into the reaction with Grigꢀ
nard reagents with subsequent trifluoromethylation of the
intermediate enamines to form tetrahydropyridines 11a,b
as a mixture of stereoisomers (Scheme 5). It should be
noted that no products 12 are formed in the reaction mixꢀ
ture, which could have been obtained by protonation of
enamines at the C(5) atom.
Scheme 3
In conclusion, we suggested a simple method for the
synthesis of CF3ꢀsubstituted 1,2,3,4ꢀtetrahydroisoquinoꢀ
lines and 1,2,3,6ꢀtetrahydropyridines using nucleophilic
trifluoromethylation reaction under acidic conditions. The
method gives products in moderate yields, however, availꢀ
ability of starting heterocyclic compounds makes this apꢀ
Trifluoromethylation of enamine 4, obtained by reꢀ
duction of salt 5, yielded an equimolar mixture of comꢀ
Table 1. Synthesis of 3ꢀtrifluoromethylꢀ1,2,3,4ꢀtetrahydroisoquinolines 3
Entry
R1
X
1
R2M
3
R2
trans : cis Yield of 3a (%)
1
2
3
4
5
Me
Me
Me
Me
PMBd
I
I
I
I
Cl
1a
1a
1a
1a
1b
MeMgI
PriMgCl/LiCl
LiEt3BH
PhMgCl
PriMgCl/LiCl
3a
3b
3c
3d
3e
Me
Pri
H
Ph
Pri
1 : 1
1 : 1
—
1.5 : 1
1.3 : 1
50b
64b
17c (13)b
52c
54b
a The yield was calculated on two steps.
b Trifluoromethylation was performed with purified enamine.
c Trifluoromethylation was performed with unpurified enamine.
d PMB is pꢀmethoxybenzyl.

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Chernyshov et al.
Scheme 4
Scheme 5
ether was distilled over LiAlH4. 4ꢀPhenylisoquinoline15 and
4ꢀmethoxybenzyl chloride (PMBCl)16 were obtained according
to the known procedures. Other commercially available reagents
were used as purchased.
2ꢀMethylisoquinolinium iodide (1a).17 Methyl iodide (1.69 mL,
27.2 mmol) was added to a solution of isoquinoline (2.80 g,
21.7 mmol) in diethyl ether (3.0 mL) under argon. The reaction
flask was tightly capped and kept for 48 h at 35—40 °C. A precipꢀ
itate formed was washed with diethyl ether (3×10 mL) and dried
in vacuo. The yield was 5.29 g (90%), yellow crystals.
2ꢀMethylꢀ4ꢀphenylisoquinolinium iodide (5). Methyl iodide
(310 μL, 4.98 mmol) was added to a solution of 4ꢀphenylisoquinꢀ
oline (452 mg, 2.20 mmol) in acetonitrile (4.5 mL) under argon
at 0 °C. The mixture obtained was kept for 64 h at 35—40 °C.
A precipitate formed was washed with diethyl ether (3×10 mL)
and dried in vacuo. The yield was 711 mg (93%), light brown
crystals, m.p. 179—180 °C. Found (%): C, 55.37; H, 3.93;
N, 3.91. C16H14IN. Calculated (%): C, 55.35; H, 4.06; N, 4.03.
1H NMR (300 MHz, CDCl3), δ: 4.81 (s, 3 H, Me); 7.48—7.66
(m, 5 H, Ph); 7.89—7.99 (m, 1 H, Ar); 7.99—8.10 (m, 2 H, Ar);
8.44 (s, 1 H, Ar); 8.71 (d, 1 H, Ar, J = 8.2 Hz); 10.78 (s, 1 H, Ar).
13C NMR (75 MHz, CDCl3), δ: 49.1, 125.2, 128.0, 129.3, 129.9,
130.0, 131.2, 131.4, 132.5, 134.0, 136.3, 137.1, 139.3, 149.0.
2ꢀ(4ꢀMethoxybenzyl)isoquinolinium chloride (1b).18 4ꢀMethꢀ
oxybenzyl chloride (7.62 μL, 5.60 mmol) was added to a solution
of isoquinoline (631 μL, 5.33 mmol) in toluene (2.5 mL). The
reaction mixture was refluxed for 1 h and cooled, toluene was
evaporated in vacuo. The product was recrystallized from ethanol.
The yield was 1.17 g (77%), light pink crystals.
10: Ar = Ph, X = Br (a); Ar = 4ꢀMeOC6H4, X = Cl (b);
11: Ar = Ph, R = Ph, 57% yield, dr (ratio of diastereomers) =
= 1.5 : 1 (a); Ar = 4ꢀMeOC6H4, R = Me, 34% yield,
dr = 1.3 : 1 (b).
proach competitive (as compared to the earlier described
methods).
1ꢀBenzylꢀ4ꢀmethylpyridinium bromide (10a).19 Benzyl bromide
(837 mL, 7.00 mmol) was added to a solution of 4ꢀpicoline
(565 μL, 7.00 mmol) in acetonitrile (0.7 mL). The mixture obꢀ
tained was kept for 3 h at 45 °C. A precipitate formed was washed
with diethyl ether (3×10 mL) and dried in vacuo. The yield was
1.73 g (99%), white crystals.
1ꢀ(4ꢀMethoxybenzyl)ꢀ4ꢀmethylpyridinium chloride (10b).
4ꢀPicoline (934 μL, 11.57 mmol) was added to PMBCl (788 μL,
5.79 mmol). The mass obtained was stirred for 3 h at 60 °C with
a reflux condenser. The picoline excess was evaporated in vacuo,
the residue was washed with diethyl ether (3×10 mL) and dried
Experimental
1
H, 13C, and 19F NMR spectra were recorded on a Bruker
AMꢀ300 or Bruker AMꢀ200 spectrometers in CDCl3. When
NMR spectra of diastereomeric mixtures were described, the
signals for two diastereomers were distinguished using the´ sign.
Tetrahydrofuran was distilled over Na/benzophenone directly
before use; DMF was distilled in vacuo over P2O5 and kept over
molecular sieves 4 Å. Acetonitrile was first distilled over P2O5,
then over CaH2 and kept over molecular sieves 4 Å. Diethyl

CF3ꢀSubstituted amines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 11, November, 2010 2105
in vacuo to obtain glassy hygroscopic compound (1.23 g, 90%).
1H NMR (300 MHz, CDCl3), δ: 2.52 (s, 3 H, MeC); 3.69 (d, 3 H,
OMe, J = 2.3 Hz); 6.12 (s, 2 H, CH2); 6.75—6.81 (m, 2 H, Ar);
7.65 (d, 2 H, Ar, J = 8.2 Hz); 7.71 (d, 2 H, CHPy, J = 6.2 Hz);
9.55 (d, 2 H, CHPy, J = 6.2 Hz). 13C NMR (75 MHz, CDCl3), δ:
22.0, 55.3, 62.8, 114.7, 125.6, 128.6, 131.2, 144.2, 158.5, 160.5.
Reaction of isoquinolinium salts with Grignard reagents (genꢀ
eral procedure).20 Grignard reagent (1.5 mmol, a solution in
THF for PhMgCl and PriMgCl/LiCl or a solution in Et2O for
MeMgI) was added dropwise to a suspension of isoquinolinium
salt 1 (1.0 mmol) and LiCl (64 mg, 1.5 mmol) in THF (2 mL)
under argon at –78 °C. The temperature was increased to ~20 °C
over 30 min and the mixture was kept for another 1.5 h at 25 °C.
Methanol (0.2 mL, 5.0 mmol) was carefully added dropwise to
the reaction mixture. The solvent was two third evaporated
in vacuo, followed by extraction with pentane (3×5 mL). Comꢀ
bined extracts were concentrated in vacuo.
1,2ꢀDimethylꢀ1,2ꢀdihydroisoquinoline (2a). The residue was
distilled in vacuo to obtain colorless oil, 67%. 1H NMR
(300 MHz, CDCl3), δ: 1.27 (d, 3 H, CHMe, J = 6.8 Hz); 2.96
(s, 3 H, NMe); 4.42 (q, 1 H, CHMe, J = 6.4 Hz); 5.22 (d, 1 H,
NCHCH, J = 6.8 Hz); 5.98 (d, 1 H, NCH, J = 6.8 Hz); 6.86
(d, 2 H, Ar, J = 7.3 Hz); 6.91—7.16 (m, 2 H, Ar).
1ꢀIsopropylꢀ2ꢀmethylꢀ1,2ꢀdihydroisoquinoline (2b). The resiꢀ
due was distilled in vacuo to obtain colorless oil, 76%. 1H NMR
(300 MHz, CDCl3), δ: 0.91 (d, 3 H, CHMeAMeB, J = 6.8 Hz);
1.00 (d, 3 H, CHMeAMeB, J = 6.8 Hz); 2.00—2.21 (m, 1 H,
CHMe2); 3.09 (s, 3 H, NMe); 4.08 (d, 1 H, PriCH, J = 6.8 Hz);
5.23 (d, 1 H, NCHCH, J = 6.8 Hz); 6.16 (d, 1 H, NCH, J = 6.8 Hz);
6.81—6.96 (m, 2 H, Ar); 6.96—7.20 (m, 2 H, Ar).
2ꢀMethylꢀ1ꢀphenylꢀ1,2ꢀdihydroisoquinoline (2d). The resiꢀ
due was recrystallized from hexane to obtain light brown crysꢀ
tals, 87%. 1H NMR (300 MHz, CDCl3), δ: 2.75 (s, 3 H, NMe);
5.27 (d, 1 H, NCHCH, J = 7.3 Hz); 5.42 (s, 1 H, PhCH); 6.22
(d, 1 H, NCHCH, J = 7.3 Hz); 6.77 (d, 1 H, Ar, J = 8.0 Hz);
6.86—7.00 (m, 2 H, Ar); 7.02—7.18 (m, 1 H, Ar); 7.24—7.50
(m, 5 H, Ar).
Reaction of isoquinolinium salts with lithium triethylboroꢀ
hydride (general procedure). A solution of Li[HBEt3] in THF
(1 M, 1.25 mL, 1.25 mmol) was added dropwise to a suspension
of isoquinolinium salt 1 (1.0 mmol) in THF (1 mL) under argon
at –25 °C. The temperature was increased to ~20 °C over 30 min
and the mixture was kept for another 1.5 h at 25 °C. The solvent
was evaporated in vacuo, the residue was extracted with pentane
(3×5 mL). Combined extracts were concentrated in vacuo.
1,2ꢀDimethylꢀ1,2ꢀdihydroisoquinoline (2c). The residue was
distilled in vacuo to obtain colorless oil, 53%. 1H NMR (300 MHz,
CDCl3), δ: 2.78 (s, 3 H, NMe); 4.20 (s, 2 H, CH2); 5.33 (d, 1 H,
NCHCH, J = 7.3 Hz); 6.10 (d, 1 H, NCH, J = 7.3 Hz);
6.84—7.20 (m, 4 H, Ar).
Reaction of pyridinium salts with Grignard reagents (general
procedure).20 A solution of the corresponding Grignard reagent
(1.5 mmol) was added dropwise to a suspension of pyridinium
salt 5 (1.0 mmol) in diethyl ether (2 mL) under argon at –25 °C.
The temperature was increased to ~20 °C over 30 min and the
mixture was kept for another 1.5 h at 25 °C. A 30% aqueous
NaOH (0.4 mL, 4.0 mmol) was carefully added dropwise to the
reaction mixture obtained. The solvent was two third evaporated
in vacuo, followed by extraction with pentane (3×5 mL). Comꢀ
bined extracts were concentrated in vacuo, the residue was used
in further transformations without purification.
Trifluoromethylation reaction of enamines (general procedure).
Potassium hydrogen difluoride (117 mg, 1.5 mmol), acetonitrile
(2 mL), and DMF (232 μL, 3.0 mmol) were sequentially added
to a enamine (1.0 mmol). Then, the mixture was cooled to 0 °C,
followed by a dropwise addition of TfOH (142 μL, 1.6 mmol),
and it was kept for 5 min at 0 °C with stirring. After addition of
Me3SiCF3 (0.44 mL, 3.0 mmol), the cooling bath was removed
and the reaction mixture was stirred for 18 h at ~20 °C. Saturated
aq. Na2CO3 (0.5 mL) was added dropwise to the mixture obꢀ
tained, which was stirred for 2 min, diluted with water (7 mL),
and extracted with the ester—hexane (1 : 1) solvent mixture
(3×5 mL). Combined extracts were filtered through Na2SO4 and
concentrated in vacuo. The residue was subjected to chromatoꢀ
graphy on silica gel.
1,2ꢀDimethylꢀ3ꢀtrifluoromethylꢀ1,2,3,4ꢀtetrahydroisoquinoꢀ
line (3a). Found (%): C, 62.72; H, 6.15; N, 6.14. C12H14F3N.
Calculated (%): C, 62.87; H, 6.16; N, 6.11. cisꢀIsomer, oil. Chroꢀ
matography: hexane—EtOAc (25 : 1), Rf 0.25. 1H NMR
(300 MHz, CDCl3), δ: 1.46 (d, 3 H, CHCH3, J = 7.0 Hz); 2.54
(s, 3 H, NMe); 2.96 (dd, 1 H, CHAHB, J = 15.7 Hz, J = 7.0 Hz);
3.05 (dd, 1 H, CHAHB, J = 15.7 Hz, J = 9.6 Hz); 3.13—3.28
(m, 1 H, CHCF3); 3.92 (q, 1 H, CHCH3, J = 7.0 Hz); 7.15—7.30
(m, 4 H, Ar). 13C NMR (75 MHz, CDCl3), δ: 22.0, 25.9 (q, J =
= 2.5 Hz); 44.1 (q, J = 1.4 Hz); 60.1, 62.3 (q, J = 28.4 Hz);
126.2, 126.5 (q, J = 282.0 Hz); 126.9, 128.1, 132.2, 140.0.
19F NMR (282 MHz, CDCl3), δ: –75.9 (d, 3 F, J = 6.4 Hz).
transꢀIsomer, oil. Chromatography: hexane—EtOAc (25 : 1),
Rf 0.19. 1H NMR (300 MHz, CDCl3), δ: 1.49 (d, 3 H, CHCH3,
J = 6.8 Hz); 2.40 (s, 3 H, NMe); 2.90—3.02 (m, 2 H, CH2); 3.46
(qdd, 1 H, CHCF3, J = 7.7 Hz, J = 6.6 Hz, J = 6.6 Hz); 3.92
(q, 1 H, CHMe, J = 6.9 Hz); 7.10—7.29 (m, 4 H, Ar). 13C NMR
(75 MHz, CDCl3), δ: 19.7, 25.0 (q, J = 2.1 Hz); 38.8 (q, J = 1.4 Hz);
57.1, 58.3 (q, J = 27.8 Hz); 126.2, 126.6, 126.7 (q, J = 284.3 Hz);
128.2, 131.8, 139.1. 19F NMR (282 MHz, CDCl3), δ: –73.1
(d, 3 F, J = 7.7 Hz).
1ꢀIsopropylꢀ2ꢀmethylꢀ3ꢀtrifluoromethylꢀ1,2,3,4ꢀtetrahydroꢀ
isoquinoline (3b). Found (%): C, 65.54; H, 7.07; N, 5.27.
C14H18F3N. Calculated (%): C, 65.35; H, 7.05; N, 5.44.
cisꢀIsomer, oil. Chromatography: hexane—EtOAc (75 : 1),
Rf 0.38. 1H NMR (300 MHz, CDCl3), δ: 0.68 (d, 3 H, CHMeAMeB,
J = 6.6 Hz); 1.22 (d, 3 H, CHMeAMeB, J = 6.6 Hz); 1.75 (septd,
1 H, CHMe2, J = 8.5 Hz, J = 6.6 Hz); 2.57 (s, 3 H, NMe);
2.82—2.98 (m, 4 H, CH2 + PriCH + CHCF3); 7.02—7.10 (m, 1 H,
Ar); 7.14—7.29 (m, 3 H, Ar). 13C NMR (75 MHz, CDCl3), δ:
20.7, 20.9, 26.5 (q, J = 2.9 Hz); 33.6, 48.7 (q, J = 1.0 Hz); 63.5
(q, J = 28.6 Hz); 74.5, 96.4, 126.3, 126.7 (q, J = 280.6 Hz);
127.1, 127.8, 128.7, 132.5, 138.7. 19F NMR (282 MHz, CDCl3),
δ: –77.04 (d, 3 F, J = 5.3 Hz). transꢀIsomer, oil. Chromatoꢀ
1
graphy: hexane—EtOAc (75 : 1), Rf 0.21. H NMR (300 MHz,
CDCl3), δ: 1.04 (d, 3 H, CHMeAMeB, J = 6.6 Hz); 1.14 (d, 3 H,
CHMeAMeB, J = 7.0 Hz); 2.02 (septd, 1 H, CHMe2, J = 6.6 Hz,
J = 2.2 Hz); 2.25 (s, 3 H, NMe); 2.88 (dd, 1 H, CHAHB, J = 10.0 Hz,
J = 6.4 Hz); 2.96 (dd, 1 H, CHAHB, J = 10.0 Hz, J = 6.0 Hz);
3.19 (d, 1 H, PriCH, J = 8.8 Hz); 3.38—3.55 (m, 1 H, CHCF3);
7.08—7.21 (m, 4 H, Ar). 13C NMR (75 MHz, CDCl3), δ: 20.4,
21.1, 24.3 (q, J = 2.0 Hz); 38.4 (q, J = 1.5 Hz); 57.8 (q, J = 29.0 Hz);
69.2, 96.5, 126.0, 126.6 (q, J = 282.5 Hz); 126.8, 128.1, 128.8,
132.9, 136.8. 19F NMR (282 MHz, CDCl3), δ: –73.2 (s, 3 F).
2ꢀMethylꢀ3ꢀtrifluoromethylꢀ1,2,3,4ꢀtetrahydroisoquinoline
(3c), oil. Chromatography: hexane—EtOAc (15 : 1), Rf 0.17.
Found (%): C, 61.31; H, 5.59; N, 6.30. C11H12F3N. Calculated (%):

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Chernyshov et al.
C, 61.39; H, 5.62; N, 6.51. 1H NMR (300 MHz, CDCl3), δ: 2.56
(q, 3 H, NCH3, J = 1.1 Hz); 2.92 (dd, 1 H, (F3C)CHCHAHB,
J = 16.0 Hz, J = 6.5 Hz); 3.10 (dd, 1 H, (F3C)CHCHAHB,
J = 16.0 Hz, J = 6.5 Hz); 3.28 (qdd, 1 H, CHCF3, J = 7.9 Hz,
J = 6.5 Hz, J = 6.5 Hz); 3.75 (d, 1 H, NCHAHB, J = 15.2 Hz);
3.95 (d, 1 H, NCHAHB, J = 15.2 Hz); 7.07—7.29 (m, 4 H, Ar).
13C NMR (75 MHz, CDCl3), δ: 26.9 (q, J = 2.3 Hz); 43.9 (q, J =
= 1.3 Hz); 54.1, 60.5 (q, J = 27.2 Hz); 126.3, 126.4, 126.9
(q, J = 285.4 Hz); 126.9, 128.0, 132.2, 134.8. 19F NMR (282 MHz,
CDCl3), δ: –73.0 (d, 3 F, J = 7.9 Hz).
J = 13.9 Hz); 3.55—3.72 (m, 2 H, PhCHAHB + CF3CH); 3.87
(d, 1 H, PhCHAHB´, J = 15.4 Hz); 3.96—4.07 (m, 2 H,
PhCHAHB´ + PhCH´); 4.12—4.24 (m, 1 H, CF3CH´); 4.57 (dd,
1 H, PhCH, J = 11.7 Hz, J = 3.7 Hz); 5.56 (s, 2 H, =CH +
+ =CH´); 7.15—7.72 (m, 20 H, 10 CHAr + 10 CHAr´). 13C NMR
(75 MHz, CDCl3), δ: 23.1, 24.0, 27.6, 39.7, 50.8, 56.3
(q, J = 2.2 Hz); 56.6, 58.9 (q, J = 28.8 Hz); 60.0 (q, J = 28.8 Hz);
60.9, 112.9, 114.6 (q, J = 2.2 Hz); 126.0 (q, J = 283.1 Hz); 126.6
(q, J = 283.1 Hz); 126.1, 127.2, 127.3, 127.6, 127.7, 127.8, 128.2,
128.2, 128.3, 128.6, 128.7, 129.5, 137.1, 138.8, 139.5, 140.8,
141.2, 144.8. 19F NMR (282 MHz, CDCl3), δ: –72.7 (d, 3 F´,
J = 8.5 Hz); –75.5 (d, 3 F, J = 8.5 Hz).
1ꢀ(4ꢀMethoxybenzyl)ꢀ2,4ꢀdimethylꢀ6ꢀtrifluoromethylꢀ1,2,3,6ꢀ
tetrahydropyridine (11b), a mixture of two diastereomers (1.5 : 1),
oil. Chromatography: hexane—EtOAc (25 : 1), Rf 0.31.
Found (%): C, 64.32; H, 6.71; N, 4.73. C16H20F3NO. Calculatꢀ
ed (%): C, 64.20; H, 6.73; N, 4.68. 1H NMR (300 MHz, CDCl3),
δ: 1.05 (d, 3 H, CHCH3, J = 6.6 Hz); 1.27 (d, 3 H, CHCH3´,
J = 6.6 Hz); 1.81 (s, 6 H, =CMe + =CMe´); 1.72—2.24 (m, 4 H,
CHCH2 + CHCH2´); 2.92—3.05 (m, 1 H, MeCH); 3.26 (d, 1 H,
NCHAHB, J = 13.2 Hz); 3.33—3.53 (m, 1 H, CF3CH); 3.66—3.98
(m, 5 H, MeCH´ + CF3CH´ + NCHAHB + NCHAHB´); 3.83
(s, 6 H, OMe + OMe´); 5.38 (s, 1 H, CH); 5.47 (s, 1 H, CH´);
6.83—6.93 (m, 4 H, 2 HAr + 2 HAr´); 7.25—7.35 (m, 4 H,
2 HAr + 2 HAr´). 13C NMR (75 MHz, CDCl3), δ: 18.5, 21.5,
23.6, 23.9, 32.4, 33.6, 48.7 (q, J = 2.3 Hz); 49.4, 49.6, 55.2,
59.1 (q, J = 28.8 Hz); 59.8, 60.6 (q, J = 28.8 Hz); 112.3, 113.1,
113.6, 126.0 (q, J = 282.5 Hz); 126.1 (q, J = 282.5 Hz); 129.4,
129.8, 131.2, 131.6, 137.8, 139.7, 158.7, 158.8. 19F NMR
(282 MHz, CDCl3), δ: –72.8 (d, 3 F´, J = 8.5 Hz); –75.3 (d, 3 F,
J = 8.5 Hz).
2ꢀMethylꢀ4ꢀphenylꢀ1ꢀtrifluoromethylꢀ1,2ꢀdihydroisoquinoꢀ
line (6). Potassium fluoride (82 mg, 1.5 mmol) and Me3SiCF3
(221 μL, 1.5 mmol) were added to a solution of salt 5 (347 mg,
1 mmol) in DMF (2 mL). The suspension obtained was stirred
for 4 h at ~20 °C, followed by a dropwise addition of saturated
aq. Na2CO3 (0.5 mL), the stirring was continued for another
2 min, then, the mixture was diluted with water (7 mL) and
extracted with the diethyl ether—hexane (1 : 1) solvent mixture
(3×5 mL). Combined extracts were filtered through Na2SO4 and
concentrated in vacuo. The yield was 91%, light brown oil.
1H NMR (300 MHz, CDCl3), δ: 3.24 (s, 3 H, NMe); 4.92 (q, 1 H,
CHCF3, J = 7.3 Hz); 6.41 (s, 1 H, NCH); 7.25—7.46 (m, 5 H,
Ar); 7.47—7.57 (m, 4 H, Ar). 13C NMR (75 MHz, CDCl3), δ:
42.4, 63.5 (q, J = 29.9 Hz); 112.6, 120.6, 122.3, 125.8, 125.9
(q, J = 292.5 Hz); 126.4, 128.6, 128.7, 129.2, 129.3, 133.9, 134.9,
138.4. 19F NMR (282 MHz, CDCl3), δ: –76.2 (d, 3 F, J = 7.9 Hz).
2ꢀMethylꢀ1ꢀphenylꢀ3ꢀtrifluoromethylꢀ1,2,3,4ꢀtetrahydroisoꢀ
quinoline (3d). Found (%): C, 70.32; H, 5.31; N, 4.75. C17H16F3N.
Calculated (%): C, 70.09; H, 5.54; N, 4.81. cisꢀIsomer, oil. Chroꢀ
matography: hexane—EtOAc (30 : 1), Rf 0.33. 1H NMR
(300 MHz, CDCl3), δ: 2.59 (s, 3 H, NCH3); 2.91 (dd, 1 H,
CHAHB, J = 15.4 Hz, J = 7.3 Hz); 3.04 (dd, 1 H, CHAHB,
J = 15.4 Hz, J = 5.5 Hz); 3.32 (m, 1 H, CHCF3); 4.62 (s, 1 H,
CHPh); 6.80 (d, 1 H, Ar, J = 7.5 Hz); 7.16—7.42 (m, 8 H, Ar).
13C NMR (75 MHz, CDCl3), δ: 27.7 (q, J = 2.5 Hz); 45.1 (q, J =
= 1.5 Hz); 62.6 (q, J = 28.2 Hz); 68.2, 126.4 (q, J = 282.5 Hz);
126.5, 127.2, 127.3, 127.3, 127.5, 128.3, 128.6, 133.4, 138.9,
142.7. 19F NMR (282 MHz, CDCl3), δ: –74.9 (d, 3 F, J = 7.5 Hz).
transꢀIsomer, oil. Chromatography: hexane—EtOAc (30 : 1),
1
Rf 0.22. H NMR (300 MHz, CDCl3), δ: 2.60 (q, 3 H, NCH3,
J = 1.8 Hz); 3.18 (dd, 1 H, CHAHB, J = 16.6 Hz, J = 4.2 Hz);
3.45 (dd, 1 H, CHAHB, J = 16.6 Hz, J = 5.9 Hz); 3.79 (m, 1 H,
CHCF3); 4.97 (s, 1 H, CHPh); 6.91 (d, 1 H, Ar, J = 7.4 Hz);
7.15 (m, 1 H, Ar); 7.23 (m, 2 H, Ar); 7.38 (m, 5 H, Ar). 13C NMR
(75 MHz, CDCl3), δ: 27.7 (q, J = 1.7 Hz); 40.8 (q, J = 1.5 Hz);
58.3 (q, J = 25.9 Hz); 66.7, 126.3, 126.4, 127.5, 127.5 (q,
J = 291.9 Hz); 128.4, 128.5, 128.6, 128.9, 130.6, 137.0, 144.2.
19F NMR (282 MHz, CDCl3), δ: –68.0 (d, 3 F, J = 8.5 Hz).
1ꢀIsopropylꢀ2ꢀ(4ꢀmethoxybenzyl)ꢀ3ꢀtrifluoromethylꢀ1,2,3,4ꢀ
tetrahydroisoquinoline (3e), a mixture of two diastereomers
(1.3 : 1), oil. Chromatography: hexane—EtOAc (20 : 1), Rf 0.33.
Found (%): C, 69.65; H, 6.81; N, 3.71. C21H24F3NO. Calculatꢀ
ed (%): C, 69.40; H, 6.66; N, 3.85. 1H NMR (300 MHz, CDCl3),
δ: 0.66 (d, 3 H, CHMeAMeB, J = 6.6 Hz); 1.00 (d, 3 H,
CHMeAMeB, J = 6.6 Hz); 1.10 (d, 3 H, CHMe´AMe´B, J = 6.6 Hz);
1.25 (d, 3 H, CHMe´AMe´B, J = 6.6 Hz); 1.80—1.96 (m, 1 H,
CHMe2); 2.06—2.22 (m, 1 H, CH´Me2); 3.00—3.60 (m, 10 H,
NCH2 + NCH´2 + CH2 + CH´2 + CHCF3 + CH´CF3); 3.86
(d, 1 H, PriCH, J = 13.2 Hz); 3.90 (s, 3 H, OCH´3); 3.92 (s, 3 H,
OCH3); 4.07 (d, 1 H, PriCH´, J = 13.2 Hz); 6.96—7.06 (m, 4 H,
2 CHAr + 2 CH´Ar); 7.17—7.28 (m, 4 H, 2 CHAr + 2 CH´Ar);
7.30—7.46 (m, 8 H, 4 CHAr + 4 CH´Ar). 13C NMR (75 MHz,
CDCl3), δ: 20.3, 20.7, 20.8, 24.2, 26.1 (q, J = 2.3 Hz); 31.6, 32.0,
51.6, 54.4, 54.8, 55.0, 55.2, 55.5, 62.8 (q, J = 28.8 Hz); 63.5,
65.9, 67.7, 113.5, 113.6, 125.7, 126.2, 126.6, 126.7 (q, J = 282.9 Hz);
126.8 (q, J = 281.9 Hz); 127.0, 127.9, 128.8, 129.0, 130.3, 130.7,
131.0, 131.4, 132.8, 132.9, 136.4, 139.0, 158.9, 159.0. 19F NMR
(282 MHz, CDCl3), δ: –71.4 (s, 3 F´); –77.0 (s, 3 F).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 08ꢀ03ꢀ00428)
and the Federal Program "Science and ScienceꢀEducaꢀ
tion Specialists of Innovative Russia" (State Contract
02.740.11.0258).
1ꢀBenzylꢀ4ꢀmethylꢀ2ꢀphenylꢀ6ꢀtrifluoromethylꢀ1,2,3,6ꢀtetꢀ
rahydropyridine (11a), a mixture of two diastereomers (1.5 : 1),
oil. Chromatography: hexane—EtOAc (30 : 1), Rf 0.38. Found (%):
C, 72.40; H, 6.19; N, 4.14. C20H20F3N. Calculated (%): C, 72.19;
H, 6.08; N, 4.23. 1H NMR (300 MHz, CDCl3), δ: 1.85 (s, 3 H,
Me); 1.98 (s, 3 H, Me´); 2.11 (dd, 1 H, CHAHB, J = 16.3 Hz,
J = 3.7 Hz); 2.29 (dd, 1 H, CHA´HB, J = 16.9 Hz, J = 3.7 Hz);
2.44 (dd, 1 H, CHAHB, J = 16.3 Hz, J = 11.7 Hz); 2.63 (dd, 1 H,
CHAHB´, J = 16.1 Hz, J = 11.7 Hz); 3.32 (d, 1 H, PhCHAHB,
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Received September 23, 2010