α-Trifluoromethyl-β-aryl enamines in the synthesis of trifluoromethylated heterocycles by the Fischer and the Pictet-Spengler reactions

Article abstract of DOI:10.1016/j.tet.2009.06.120

α-Trifluoromethyl-β-aryl enamines were successfully used as synthetic equivalents of benzyltrifluoromethyl ketones in both the Fischer indole synthesis and the Pictet-Spengler reaction. Accordingly, 2-trifluoromethyl indoles and a variety of trifluorometh

Full text of DOI:10.1016/j.tet.2009.06.120

Tetrahedron 65 (2009) 7553–7561
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
a-Trifluoromethyl-b-aryl enamines in the synthesis of trifluoromethylated
heterocycles by the Fischer and the Pictet–Spengler reactions
,
b
Vasiliy M. Muzalevskiy a, Valentine G. Nenajdenko a , Aleksey V. Shastin ,
*
,
Elizabeth S. Balenkova a, Gu¨nter Haufe c
*
a Moscow State University, Department of Chemistry, Leninskie Gory, Moscow 119992, Russia
b Institute of Problems of Chemical Physics, Chernogolovka, Moscow Region 142432, Russia
c Organisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t Mu¨nster, D-48149 Mu¨nster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 May 2009
Received in revised form 14 June 2009
Accepted 29 June 2009
Available online 3 July 2009
a
-Trifluoromethyl-b-aryl enamines were successfully used as synthetic equivalents of benzyltri-
fluoromethyl ketones in both the Fischer indole synthesis and the Pictet–Spengler reaction. Accordingly,
2-trifluoromethyl indoles and a variety of trifluoromethylated 4,5,6,7-terahydro-1H-pyridines including
carbolines were synthesized in moderate to good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
a
-Trifluoromethyl-b-aryl enamines
Fischer indole synthesis
Pictet–Spengler reaction
Indoles
Tetrahydropyridines
Carbolines
1. Introduction
The tendency of trifluoromethylated carbonyl compounds to
form stable semiaminals is well known resulting in some difficul-
Fluorine-containing compounds have been object of intensive
research in recent decades1 due to the unique complex of physical
and biological properties provided by fluorine substituents.2 As
a result, an enormous progress in this field has been achieved.3
Previously, we successfully applied nucleophilic vinylic sub-
ties of their further transformation. On the other hand, secondary
amino groups such as the pyrrolidino moiety are good leaving
groups in acidic media. Consequently,
a-trifluoromethyl-b-aryl
enamines are expected to be convenient synthetic equivalents of
the parent carbonyl compounds and we became attracted to use
this strategy for the synthesis of trifluoromethylated indoles,
stitution of halogen in
b
-chloro-4 and
-trifluoromethyl-
b
-bromo-
b
-(trifluoromethyl)-
styrenes5 1 for the synthesis of
a
b
-aryl enamines.6
tetrahydroisoquinolines and b
-carbolines by Fischer7 and Pictet–
The latter compounds do attract a special interest due to the ob-
vious possibility to react as ketone equivalents (Scheme 1).
Spengler8 reactions, respectively. Elaboration of new indole syn-
theses9 as well as syntheses of heterocycles with an annulated
tetrahydropyridine ring raised great interest due to the manyfold
biological activity of their derivatives. Numerous natural alkaloids
and drugs do contain these basic skeletons.10–12 On the other hand,
the introduction of fluorine into organic compounds is a well-
known strategy to enhance their physiological activity.2,3c,13 Not
surprising, trifluoromethylated indoles have been involved as core
structures for the design of pharmaceutically important mole-
cules,14 and a number of pathways for their synthesis was elabo-
rated in recent decades. These include direct perfluoroalkylations
by perfluoroalkylhalides15–17 and perfluoroalkanoyl peroxides,18,19
thermolysis of 2-(N-trifluoroacetylamino)benzylphosphonium
salts,20 intramolecular cyclization of N-trifluoroacetyl-p-benzo-
quinones,21 palladium-catalyzed annulation of fluorine-containing
internal alkynes with various substituted 2-iodoanilines,22
CF3
CF3
HN
X
N
68-98%
Ar
Ar
X = Cl, Br
1
2
Scheme 1. Synthesis of
a-trifluoromethyl-b-aryl enamines 2.
* Corresponding authors. Tel.: þ7 495 9392276; fax: þ7 495 9328846 (V.G.N.);
tel.: þ49 251 83 33281; fax: þ49 251 83 39772 (G.H.).
E-mail addresses: nen@acylium.chem.msu.ru (V.G. Nenajdenko), shastin@icp.
ac.ru (A.V. Shastin), haufe@uni-muenster.de (G. Haufe).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.120

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V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 7553–7561
Table 1
titanium-catalyzed carbonyl coupling of 2-acyl-trifluoroace-
tanilides,23 the Grignard cyclization reaction of fluorinated N-ary-
limidoyl chlorides24 and the reaction of the N-trimethylsilyltoluidine
dianion with ethyl trifluoroacetate.25 Furthermore, several Cu cata-
lyzed reactions such as Cu (I) catalyzed nucleophilic substitution of
Synthesis of 3-aryl-2-trifluoromethyl indoles 5
Indole 5 Ar R1 R2 Yield (%) Indole 5 Ar
R1
R2 Yield (%)
a
b
c
d
e
f
4-NO2C6H4
4-ClC6H4
Ph
4-MeCO2C6H4
2-BrC6H4
2-NO2C6H4
3-NO2C6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
88
68
45
43
70
45
70
h
i
j
k
l
m
n
4-ClC6H4 Cl
4-ClC6H4 F
4-ClC6H4 CN
4-ClC6H4 Me
4-ClC6H4 MeO
4-ClC6H4 Cl
H
H
H
H
H
89
69
50
76
41
vinyl and aryl halogen atoms of
bearing ortho-bromine by primary amines,26 and the CuI/
catalyzed coupling-condensation-deacylation cascade reactions of
2-halotrifluoroacetanilides with
-keto esters were developed.27
b
-halo-b-trifluoromethylstyrenes
L
-proline-
Cl 52
b
g
4-ClC6H4 Me Me 68
Though this variety, most of these approaches suffer from the lim-
ited availability of the starting materials, poor yields or low regio-
selectivity. Therefore, the development of new methods for the
preparation of trifluoromethylated heterocycles is still desirable.
different combinations of electron-donating and electron-with-
drawing substituents in the aryl or indole rings can be obtained by
this method. The Fischer reaction proceeded regioselectively
resultinginthe formation ofonlyoneregioisomer. Thehighestyields
were obtained with compounds bearing electron-withdrawing
groups (5a, 5h). This can be explained by their higher stability in
acidic media under air comparing with substrates carrying electron-
donating substituents. Performing the reactions under argon
atmosphere at 90 ꢀC led to significantly higher yields in case of
electron donating substituents. In this way the yields of the indoles
5k, 5l and 5n were increased from 29% to 76% (5k), 21% to 41% (5l)
and 23% to 68% (5n). To the best of our knowledge, these are the first
examples of the synthesis of trifluoromethyl indoles by the Fischer
synthesis starting from enamines 2. The parent trifluoromethyl-
benzyl ketones have not been used in the Fischer indole synthesis
so far.28
2. Results
2.1. Application of a-trifluoromethyl-b-aryl enamines for the
synthesis of 3-aryl-2-trifluoromethyl indoles
We assumed that the reaction of enamines 2 with arylhydrazines
3 in acidic media would led to the corresponding hydrazones.
Accordingly, refluxing the enamine 2a with phenylhydrazine in
acetic acid for 15–20 min gave the desired hydrazone 4a in almost
quantitative yield. Although some variations of the Fischer reaction
exploit heating of the intermediate hydrazones in acetic acid to give
indoles, this protocol did not work in case of the a-CF3-hydrazone 4a
even after several hours of reflux. Probably the acidity of acetic acid
is not sufficient to run the rearrangement in the presence of the CF3-
group. Addition of two equivalents of methanesulfonic acid over-
came this problem and the formation of the target indole 5a was
completed after few hours. Thus, the reaction of arylhydrazines with
2-aryl-1-trifluoromethyl enamine can be stopped on the stage of the
arylhydrazone and can be completed to the corresponding indole by
heating in the presence of a strong acid. In order to find milder
conditions for the rearrangement and toincrease theyields in case of
more acid sensitive substrates, the reaction was performed in EtOH
using SOCl2 as a catalyst, in acetic acid/TFA and toluene/TFA mix-
tures. In all cases the formation of hydrazones was observed at room
temperature, but, as well as in case of CH3SO3H, heating was needed
for the rearrangement to the indole. Less acidic catalysts led to sig-
nificant increase of the reaction time. Moreover, the yield of
the indole 5a dropped to 16–23% under the latter conditions. Thus,
quite strong acids are necessary to facilitate the Fischer reaction of
2.2. Application of a-trifluoromethyl-b-aryl enamines in the
Pictet–Spengler reaction
Succeeded in the application of
a-trifluoromethyl-b-aryl
enamines 2 in the Fischer indole synthesis, we decided to also
use these enamines in the Pictet–Spengler reaction. However,
heating of the enamines 2 with the tryptamines 6 in an ethanol-
water mixture using HCl as catalyst (classical Pictet–Spengler’s
conditions8) gave only tar, perhaps due to acid catalyzed
polymerization of the indole moiety. Carrying out this re-
action under milder conditions in CH2Cl2 using TFA as acid
overcame this problem and the corresponding 2,3,4,9-tetra-
hydro-1H-b-carbolines 7 were obtained in satisfactory yields
after a week at room temperature. This reaction is quite
general and permitted the preparation of a wide variety of
carbolines, bearing both electron-donating and electron-
withdrawing substituents in the aromatic ring of enamines 2
(Scheme 3, Table 2).
a
-CF3-hydrazones. Having found optimal conditions, we performed
a series of reactions of enamines 2 with arylhydrazines 3, varying
both the arylhydrazines and the enamine components (Scheme 2,
Table 1).
R1
Ar
R1
NH2
NH
CF3
Ar
R1
TFA
CH2Cl2, r.t.
60-75%
Ar
N
CF3
i
N
H
N
H
NH2
N
H
N
CF3
R1
R2
7
2
6
2
3
Scheme 3. Reactions of a-trifluoromethyl-b-aryl enamines 2 with tryptamines 6.
Ar
Ar
R1
CF3
ii or iii
Table 2
Synthesis of 2,3,4,9-tetrahydro-1H-
CF3
b-carbolines 7
N
N
N
H
41-89%
H
R2
R2
Comp 7
Ar
R1
Yield (%)
4
a
b
c
d
e
f
g
h
i
4-NO2C6H4
4-ClC6H4
Ph
4-MeCO2C6H4
2-BrC6H4
2-NO2C6H4
3-NO2C6H4
4-MeOC6H4
4-ClC6H4
H
H
H
H
H
H
H
H
70
63
60
70
61
66
68
67
75
5
Scheme 2. Reactions of
a-trifluoromethyl-b-aryl enamines 2 with arylhydrazines 3.
Conditions: (i) AcOH, reflux; (ii) 2 equiv CH3SO3H, reflux (5a–5j, 5m); (iii) 2 equiv
CH3SO3H, 90 ꢀC, argon atmosphere (5k, 5l, 5n).
As a result, a variety of 3-aryl-2-trifluoromethyl indoles 5 was
synthesized in moderate to high yields without isolation of the in-
termediate hydrazones 4. Trifluoromethylated indoles bearing
n-C4H9

V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 7553–7561
7555
In case of
L
-tryptophane methyl ester (8), the formation of the
(1-pyrrolyl)ethylamine (12) were performed in acetic acid, which is
four orders of magnitude weaker comparing to trifluoroacetic acid
used before. The desired 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
derivatives 13a and 13b were isolated in good yields as bright
crystals after several days of standing at room temperature
(Scheme 6).
cyclization product proceeded very slowly and in low yield under
the mentioned conditions. This might be explained by lower steric
accessibility and lower nucleophilicity of the nitrogen atom.
Refluxing the reaction mixture did not lead to a remarkable in-
crease of the reaction rate. However, replacement of CH2Cl2 with
the higher-boiling acetic acid gave the corresponding cyclic de-
rivative 9 in moderate yield as a 67:33 mixture of diastereomers,
which were not assigned (Scheme 4).
Ar
HOAc
r.t.
NH2
N
NH
CF3
Ar
N
N
CF3
O
O
OMe
NH2
13a Ar = 4-NO2C6H4
13b Ar = 4-ClC6H4
68%
70%
12
2
OMe
Ar
NH
CF3
Ar
HOAc
reflux
43%
Scheme 6. Synthesis of 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines 13a and 13b.
N
CF3
N
H
N
H
Furthermore, the reaction of 2-(3-thienyl)ethylamine (14) with
enamine 2 in acetic acid gave the 4,5,6,7-tetrahydrothieno[2,3-
c]pyridine 15 in moderate yield (Scheme 7).
8
Ar = 4-ClC6H4
2a
9
Scheme 4. Synthesis of cyclic derivative 9.
The synthesized compounds 7 and 9 are analogs of the natural
alkaloid Harman (arabine, 1-methyl-S-carboline), which has been
found in plants29 and revealed as enzyme inhibitor, mutagen and
antagonist of the benzodiazepine receptors.30 On the other hand,
due to the presence of two well known pharmacophores (the 2-
arylethylamine moiety and the CF3-group) in compounds 7, one can
expect particular biological activity, which makes them promising
objects for bioorganic chemistry. However, preliminary tests of
Ar
NH2
HOAc
NH
CF3
Ar
N
CF3
r.t.
51%
S
S
15
Ar = 4-ClC6H4
14
2a
Scheme 7. Synthesis of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine 15.
In case of histamine dihydrochloride (16), the reaction was
carried out in two steps. At first
their activity as
s
-receptor antagonists did not show significant
a mixture of histamine
effects (Fig. 1).31
dihydrochloride and enamine 2 was heated under reflux in
ethanol until the enamine was completely consumed to give an
intermediate iminium salt. Subsequently, two equivalents of KOH
were added for neutralization of the acid. Thus, cyclization to
form 17 occurred under basic conditions In acidic medium, the
imidazole ring is not active enough to be attacked electrophili-
cally (Scheme 8, Table 3).
R1
N
NH
CF3
Ar
N
H
N
H
Harman
7
Figure 1. Structures of Harman and compounds 7.
Ar
NH2
NH
CF3
Ar
In order to plumb the synthetic scope of the method we per-
formed a series of reactions of enamines 2 with several other ethyl-
amines, containing both aryl- and hetaryl substituents, activated
for electrophilic attack. For example, the reaction of 2 with
2-(3,4-diethoxyphenyl)ethylamine (10) in CH2Cl2 in the presence
of TFA at rt gave the 1,2,3,4-tetrahydroisoquinoline derivatives
11a and 11b in moderate yields (Scheme 5).
N
i, ii
N
.
2HCl
N
CF3
N
H
N
H
44-77%
17
16
2
Scheme 8. Reactions of enamines 2 with histamine dihydrochloride (16). Conditions:
(i) EtOH, reflux; (ii) 2 equiv KOH, reflux.
Table 3
Ar
EtO
EtO
EtO
EtO
Synthesis of 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridines (17)
TFA
N
CF3
NH2
NH
CF3
Compound 17
Ar
Yield (%)
CH2Cl2, r.t.
a
b
c
d
h
4-NO2C6H4
4-ClC6H4
Ph
4-MeCO2C6H4
4-MeOC6H4
66
54
77
44
45
Ar
10
2
54%
48%
11a Ar = 4-NO2C6H4
11b Ar = 4-ClC6H4
Scheme 5. Synthesis of 1,2,3,4-tetrahydroisoquinolines 11a and 11b.
Next we focused on the preparation of 1,2,3,4-tetrahydro-
pyrrolo[1,2-a]pyrazines, which are of considerable interest because
of their antiamnesic, antihypoxic,32 psychotropic,33 antihy-
persensitive,34 and aldose reductase inhibitor activities.35 Further-
more, pyrrolopyrazines do also selectively bind to GABAa receptors36
and are useful starting materials for the synthesis of octahy-
dropyrrolo-[1,2-a]pyrazine-based coronary-dilators and neuroleptics.37
Because of the well known easy polymerization of pyrroles in
acidic media, the reactions of enamines 2a and 2b with 2-
In summary, a number of substituted 4,5,6,7-tetrahydro-3H-
imidazo[4,5-c]pyridines 17, bearing either electron-withdrawing
or electron-donating substituents in the aryl ring, was obtained
from enamines 2 in moderate to good yields. The parent tri-
fluoromethylbenzyl ketones of 2 have not been used in the
Pictet–Spengler reaction yet.28 The heterocyclic core of the
synthesized compounds 17 is the alkaloid spinaceamine (4,5,6,7-
tetrahydroimidazo[4,5-c]pyridine) and a constituent of spinacine
(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid),

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V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 7553–7561
which both play an important biological role in flora and
fauna.38
bottomed flask and refluxed for 1 h. CH3SO3H (202 mg, 2.1 mmol)
was added and the reaction mixture was refluxed for another 10–
15 h until the hydrazone disappeared (TLC control). In the case of
indoles 5k, 5l, 5n the reactions were carried out under argon at-
mosphere at 90 ꢀC. Acetic acid was evaporated in vacuo, the residue
was dissolved in CH2Cl2 (30 mL), washed with saturated solution of
K2CO3 (10 mL) and dried over Na2SO4. CH2Cl2 was removed in
vacuo and the residue was purified by column chromatography on
silica gel using mixtures of CH2Cl2 and hexane as eluents.
HO
O
NH
NH
HN
HN
N
N
Spinacine
Spinaceamine
3. Conclusions
4.3.1. 3-(4-Nitrophenyl)-2-trifluoromethyl-1H-indole (5a)
Obtained from enamine 2a (286 mg, 1 mmol) and phenyl-
hydrazine (108 mg, 1 mmol). Yield: 270 mg (88%); yellow crystals;
a
-Trifluorometyl-b-aryl enamines 2 have been shown to be syn-
mp 184–185 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.28 (td, J¼7.9, 0.8 Hz,
thetic equivalents of corresponding benzyltrifluoromethyl ketones in
both the Fischer and the Pictet–Spengler reactions, although the latter
compoundshavenotbeenusedinthesereactionssofar. Theenamines
2 reacted smoothly with arylhydrazines in acetic acid to give a-CF3-
hydrazones 4. The Fischer rearrangement of trifluoromethylated
hydrazones needs stronger acids to occur but was successful in
refluxing methanesulfonic acid and
fluoromethyl indoles 5 were prepared in moderate to high yields. The
one-pot transformation of 2 to 5 wasalsoelaborated. Moreover, a new
versatile approach to polycyclic trifluoromethylated 4,5,6,7-tetrahy-
dro-1H-pyridines including carbolines was developed using the Pic-
1H, Ind), 7.44 (t, J¼7.9 Hz, 1H, Ind), 7.54 (d, J¼7.9 Hz, 1H, Ind), 7.64
(d, J¼7.9 Hz, 1H, Ind), 7.73 (d, J¼8.7 Hz, 2H, Ar), 8.37 (d, J¼8.7 Hz,
2H, Ar), 8.79 (br s, 1H, NH, Ind); 13C NMR (100 MHz, CDCl3)
d 112.1,
117.3 (q, J¼2.3 Hz, C]C–CF3), 120.4, 122.0 (q, J¼36.6 Hz, C–CF3),
122.1, 125.7, 126.6, 130.9, 134.9 (Ind), 121.1 (q, CF3, J¼268.6 Hz),
123.8, 130.7, 139.3, 147.1 (Ar). 1H NMR and 13C NMR spectra are in
agreement with the literature data.22
a series of 3-aryl-2-tri-
4.3.2. 3-(4-Chlorophenyl)-2-trifluoromethyl-1H-indole (5b)
Obtained from enamine 2b (276 mg, 1 mmol) and phenyl-
hydrazine (108 mg, 1 mmol). Yield: 201 mg (68%); yellow powder;
tet–Spengler reaction of
a-trifluorometyl-b-aryl enamines 2 with
mp 81–82 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.26 (t, J¼7.5 Hz,1H, Ind),
aryl- and hetarylamines. The thus synthesized heterocyclic com-
pounds contain three pharmacophore fragments simultaneously,
which might be interesting for biomedical investigations.
7.43 (d, J¼7.9 Hz, 1H, Ind), 7.45–7.50 (m, 5H, Ind, Ar), 7.65 (d,
J¼7.5 Hz, 1H, Ind), 8.54 (br s, 1H, NH, Ind); 13C NMR (100 MHz,
CDCl3)
d
111.9, 118.5 (q, J¼2.9 Hz, C]C–CF3), 120.6, 121.3 (q,
4. Experimental
4.1. General
J¼36.9 Hz, C–CF3), 121.5, 125.3, 130.6, 134.9 (Ind), 121.5 (q,
J¼268.6 Hz, CF3), 127.1, 128.7, 131.3, 133.5 (Ar). 1H NMR and 13C NMR
spectra are in agreement with the literature data.22
1H, 13C and 19F NMR spectra were recorded on Bruker ARX 300
and Bruker AMX 400 spectrometers in CDCl3 with TMS, and CCl3F
as internal standards. IR spectra were obtained as films. Column
and TLC chromatography were performed using silica gel Merck 60
or Merck 60F254 plates, respectively. Mass spectra were measured
on a MicroTof Bruker Daltonics (ESI-MS). Column and TLC chro-
matography were performed on silica gel Merck 60 and Merck
4.3.3. 3-Phenyl-2-trifluoromethyl-1H-indole (5c)
Obtained from enamine 2c (241 mg, 1 mmol) and phenyl-
hydrazine (108 mg, 1 mmol). Yield: 118 mg (45%); pale brown
crystals; mp 66–67 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.24 (td, J¼7.8,
0.8 Hz, 1H, Ind), 7.38–7.47 (m, 2H, Ind, Ar), 7.48–7.54 (m, 3H, Ar),
7.55–7.59 (m, 2H, Ar), 7.69 (d, J¼7.8 Hz, 1H, Ind), 8.53 (br s, 1H, NH,
Ind); 19F NMR (282 MHz, CDCl3)
d
ꢁ57.32; 13C NMR (100 MHz,
60F254 plates, respectively. The a-trifluoromethyl-b-aryl enamines
CDCl3)
d
117.7, 119.9 (q, J¼3.6 Hz, C]C–CF3), 121.1, 121.2 (q,
were synthesized according to our previously reported procedure.6
J¼37.3 Hz, C–CF3), 121.3, 125.2, 132.1, 135.0 (Ind), 121.7 (q, CF3,
J¼268.6 Hz), 127.3, 127.6, 128.4, 129.9 (Ar). ESI-MS (m/z): calcd for
C15H10F3NNa [Mþ] 284.0663, found 284.0658. Anal. Calcd for
C15H10F3N: C, 68.96; H, 3.86. Found: C, 68.95; H, 3.85.
4.2. 1,1,1-Trifluoro-3-(4-nitrophenyl)acetone
phenylhydrazone (4a)
Phenylhydrazine (120 mg, 1.05 mmol), enamine 2a and acetic
acid(5 mL)weremixedina25 mLroundbottomedflaskandrefluxed
for 1 h. Acetic acid was removed in vacuo, the residue was dissolved
in CH2Cl2 (30 mL), washed with saturated solution of K2CO3 (10 mL)
and dried over Na2SO4. CH2Cl2 was evaporated in vacuum, and the
residue was filtered through a short silica gel pad using CH2Cl2. Yield:
284 mg (88%); yellow crystals; mp 155–157 ꢀC; 1H NMR (400 MHz,
4.3.4. Methyl 4-(2-trifluoromethyl-1H-indole-3-yl)benzoate (5d)
Obtained from enamine 2d (299 mg, 1 mmol) and phenyl-
hydrazine (108 mg, 1 mmol). Yield: 137 mg (43%); pale brown
powder; mp 144–146 ꢀC; 1H NMR (400 MHz, CDCl3)
d 4.02 (s, 3H,
CO2CH3), 7.26 (t, J¼7.8 Hz, 1H, Ind), 7.42 (t, J¼7.8 Hz, 1H, Ind), 7.53
(d, J¼7.8 Hz, 1H, Ind), 7.65–7.70 (m, 3H, Ind, Ar), 8.21 (d, J¼8.3 Hz,
2H, Ar), 9.15 (br s, 1H, NH, Ind); 19F NMR (282 MHz, CDCl3)
d
ꢁ56.82; 13C NMR (100 MHz, CDCl3)
d 52.3 (CO2CH3), 112.0, 118.5
CDCl3)
d
3.97 (s, 2H, CH2), 7.00 (t, J¼7.6 Hz, 1H, Ph), 7.09 (d, J¼7.6 Hz,
2H, Ph), 7.26–7.34 (m, 2H, Ph), 7.43 (d, J¼8.5 Hz, 2H, 4-NO2C6H4–),
(q, J¼2.8 Hz, C]C–CF3), 120.7, 121.6, 121.8 (q, J¼30.7 Hz, C–CF3),
125.3, 126.9, 135.1 (Ind), 121.6 (q, J¼270.1 Hz, CF3), 129.1, 129.7,
130.0, 137.4 (Ar), 167.3 (CO2CH3). ESI-MS (m/z): calcd for
C17H12F3NO2Na [Mþ] 342.0718, found 342.0712. Anal. Calcd for
C17H12F3NO2: C, 63.95; H, 3.79. Found: C, 63.84; H, 3.72.
7.71 (d, J¼8.5 Hz, 2H, 4-NO2C6H4–), 8.18 (br s, 1H, NH); 19F NMR
(282 MHz, CDCl3):
d
ꢁ68.40; 13C NMR (100 MHz, CDCl3)
d 29.8 (CH2),
121.9 (q, J¼272.2 Hz, CF3), 128.5 (q, J¼34.4 Hz, C–CF3), 113.9, 122.4,
128.9, 141.3 (Ph), 124.4, 129.4, 142.9, 147.1 (4-NO2C6H4–). ESI-MS
(m/z): calcd for C15H12F3N3O2Na [Mþ] 346.0779, found 346.0774.
4.3.5. 3-(2-Bromophenyl)-2-trifluoromethyl-1H-indole (5e)
Obtained from enamine 2e (320 mg, 1 mmol) and phenyl-
hydrazine (108 mg, 1 mmol). Yield: 238 mg (70%); yellow viscous
4.3. Synthesis of 3-aryl-2-trifluoromethyl indoles 5 (general
procedure)
oil; 1H NMR (400 MHz, CDCl3)
d
7.29 (td, J¼7.5, 1.0 Hz, 1H, Ind),
Arylhydrazine
4
(1 mmol), the corresponding enamine
2
7.34–7.40 (m, 1H, Ind, Ar), 7.43–7.53 (m, 5H, Ind, Ar), 7.55–7.59 (m,
(1 mmol) and acetic acid (5 mL) were mixed in a 25 mL round
2H, Ar), 7.82 (d, J¼7.8 Hz, 1H, Ind), 8.54 (br s, 1H, NH, Ind); 19F NMR

V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 7553–7561
7557
(282 MHz, CDCl3)
d
ꢁ58.56; 13C NMR (100 MHz, CDCl3)
d
111.9,
7.99 (s, 1H, Ind), 9.24 (br s, 1H, NH, Ind); 19F NMR (282 MHz, CDCl3)
119.0 (q, J¼2.9 Hz, C]C–CF3), 121.4 (q, J¼269.3 Hz, CF3), 121.4, 121.5,
122.2 (q, J¼37.3 Hz, C–CF3), 125.1, 125.3, 127.1, 127.2, 129.8, 132.7,
132.8, 133.4, 134.9. ESI-MS (m/z): calcd for C15H9BrF3NNa [Mþ]
361.9768, found 361.9763. Anal. Calcd for C15H9ClF3N: C, 52.97; H,
2.67. Found: C, 53.04; H, 2.65.
d
ꢁ57.33; 13C NMR (100 MHz, CDCl3)
d 104.9 (CN), 113.1, 119.1 (q,
J¼2.9 Hz, C]C–CF3), 119.7, 123.6 (q, J¼37.3 Hz, C–CF3), 126.9, 127.0,
134.5, 136.5 (Ind), 121.0 (q, J¼269.3 Hz, CF3), 127.7, 129.1, 130.3, 131.1
(Ar). ESI-MS (m/z): calcd for C16H8ClF3N2Na [Mþ] 343.0226, found
343.0220. Anal. Calcd for C16H8ClF3N2: C, 59.92; H, 2.51. Found: C,
60.04; H, 2.62.
4.3.6. 3-(2-Nitrophenyl)-2-trifluoromethyl-1H-indole (5f)
Obtained from enamine 2f (286 mg, 1 mmol) and phenyl-
hydrazine (108 mg, 1 mmol). Yield: 138 mg (45%); yellow viscous
4.3.11. 5-Methyl-3-(4-chlorophenyl)-2-trifluoromethyl-
1H-indole (5k)
oil; 1H NMR (400 MHz, CDCl3)
d
7.19 (td, J¼7.7, 0.9 Hz, 1H, Ar), 7.30–
Obtained from enamine 2b (276 mg, 1 mmol) and (4-methyl-
phenyl)hydrazine (122 mg, 1 mmol). Yield: 236 mg (76%); green-
7.40 (m, 2H, Ind), 7.43 (d, J¼8.1 Hz, 1H, Ind), 7.54 (dd, J¼7.7, 1.3 Hz,
1H, Ar), 7.62 (dd, J¼8.1, 1.5 Hz, 1H, Ind), 7.71 (td, J¼7.7, 1.3 Hz, 1H,
Ar), 8.12 (dd, J¼7.7, 0.9 Hz, 1H, Ar), 8.72 (br s, 1H, NH, Ind); 19F NMR
yellow crystals; mp 98–99 ꢀC; 1H NMR (400 MHz, CDCl3)
d 2.48 (s,
3H, CH3), 7.25 (d, J¼8.3 Hz, 1H, Ind), 7.38 (d, J¼8.3 Hz, 1H, Ind), 7.42
(282 MHz, CDCl3)
d
ꢁ58.24; 13C NMR (100 MHz, CDCl3)
d 112.1,114.7
(s, 1H, Ind), 7.50 (s, 4H, Ar), 8.44 (br s, 1H, NH, Ind); 13C NMR
(q, J¼2.9 Hz, C]C–CF3), 120.1, 121.7, 121.8 (q, J¼38.1 Hz, C–CF3),
125.4, 127.0, 134.9 (Ind), 121.3 (q, J¼269.3 Hz, CF3), 124.6, 127.2,
129.2, 132.7, 133.6, 149.8 (Ar). ESI-MS (m/z): calcd for
C15H9F3N2O2Na [Mþ] 329.0514, found 329.0514. Anal. Calcd for
C15H9F3N2O2: C, 58.83; H, 2.96. Found: C, 58.77; H, 3.02.
(100 MHz, CDCl3)
d
21.4 (CH3), 111.5, 118.1 (q, J¼2.9 Hz, C]C–CF3),
120.1, 121.4 (q, J¼36.6 Hz, C–CF3), 121.6 (q, J¼269.3 Hz, CF3), 127.2,
127.4, 128.7, 130.9, 131.1, 131.2, 133.3, 133.6. 1H NMR and 13C NMR
spectra are in agreement with the literature data.22
4.3.12. 5-Methoxy-3-(4-chlorophenyl)-2-trifluoromethyl-
1H-indole (5l)
4.3.7. 3-(3-Nitrophenyl)-2-trifluoromethyl-1H-indole (5g)
Obtained from enamine 2g (286 mg, 1 mmol) and phenyl-
hydrazine (108 mg, 1 mmol). Yield: 214 mg (70%); yellow crystals;
Obtained from enamine 2b (276 mg, 1 mmol) and (4-methoxy-
phenyl)hydrazine (138 mg, 1 mmol). Yield: 134 mg (41%); white
mp 126–127 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.29 (td, J¼8.0, 0.8 Hz,
crystals; mp 72–73 ꢀC; 1H NMR (400 MHz, CDCl3)
d 3.83 (s, 3H,
1H, Ind), 7.45 (t, J¼8.0 Hz,1H, Ind), 7.54 (d, J¼8.0 Hz, 1H, Ind), 7.63 (d,
J¼8.0 Hz, 1H, Ind), 7.69 (t, J¼7.9 Hz, 1H, Ar), 7.89 (d, J¼7.9 Hz, 1H, Ar),
8.31 (ddd, J¼7.9, 1.9, 1.0 Hz, 1H, Ar), 8.46 (t, J¼1.9 Hz,1H, Ar), 8.86 (br s,
OCH3), 7.00 (d, J¼2.1 Hz, 1H, Ind), 7.06 (dd, J¼8.9, 2.1 Hz, 1H, Ind),
7.38 (d, J¼8.9 Hz, 1H, Ind), 7.48 (s, 4H, Ar), 8.47 (br s, 1H, NH, Ind);
19F NMR (282 MHz, CDCl3)
d
ꢁ56.84; 13C NMR (100 MHz, CDCl3)
1H, NH, Ind); 19F NMR (282 MHz, CDCl3)
d
ꢁ56.85; 13C NMR
d
55.8 (OCH3), 101.3, 112.7, 116.5, 118.1 (q, J¼2.9 Hz, C]C–CF3), 121.9
(100 MHz, CDCl3)
d
112.1, 117.0 (q, J¼2.9 Hz, C]C–CF3),120.3, 122.0 (q,
(q, J¼37.3 Hz, C–CF3), 130.8, 133.6, 155.5 (Ind), 121.5 (q, J¼269.3 Hz,
CF3), 127.6, 128.8, 130.0, 131.1 (Ar). Anal. Calcd for C16H11ClF3NO: C,
59.00; H, 3.40. Found: C, 58.78; H, 3.42.
J¼37.3 Hz, C–CF3), 122.5, 126.7, 129.5, 135.0 (Ind), 121.4 (q, J¼268.6 Hz,
CF3),122.0,124.7,125.7,134.1,136.1,148.4 (Ar). ESI-MS (m/z): calcd for
C15H9F3N2O2Na [Mþ] 329.0514, found 329.0508. Anal. Calcd for
C15H9F3N2O2: C, 58.83; H, 2.96. Found: C, 58.84; H, 2.93.
4.3.13. 5,7-Dichloro-3-(4-chlorophenyl)-2-trifluoromethyl-
1H-indole (5m)
4.3.8. 5-Chloro-3-(4-chlorophenyl)-2-trifluoromethyl-
1H-indole (5h)
Obtained from enamine 2b (276 mg, 1 mmol) and (2,4-dichloro-
phenyl)hydrazine (177 mg, 1 mmol). Yield: 190 mg (52%); white
Obtained from enamine 2b (276 mg, 1 mmol) and (4-chloro-
phenyl)hydrazine (143 mg, 1 mmol). Yield: 294 mg (89%); white
crystals; mp 101–103 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.38–7.45 (m,
3H, Ind, Ar), 7.47–7.52 (m, 3H, Ind, Ar), 8.72 (br s, 1H, NH, Ind); 13C
NMR (100 MHz, CDCl3)
crystals; mp 110–111 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.34–7.41 (m,
d
117.9, 119.2 (q, J¼2.9 Hz, C]C–CF3), 119.1,
2H, Ind), 7.62 (d, J¼0.8 Hz, 1H, Ind), 7.46 (d, J¼8.6 Hz, 2H, Ar), 7.50
119.4 (q, J¼38.1 Hz, C–CF3), 120.9 (q, J¼270.1 Hz, CF3), 124.9, 127.5,
128.7, 129.0, 129.3, 131.0, 134.4. Anal. Calcd for C15H7Cl3F3N: C,
49.42; H, 1.94. Found: C, 49.32; H, 1.82.
(d, J¼8.6 Hz, 2H, Ar), 8.60 (br s, 1H, NH, Ind); 13C NMR (100 MHz,
CDCl3)
d
113.1, 118.2 (q, J¼2.9 Hz, C]C–CF3), 120.2, 121.3 (q,
J¼270.1 Hz, CF3), 122.6 (q, J¼37.5 Hz, C–CF3), 125.9, 127.4, 128.1,
128.9, 129.9, 131.1, 133.2, 134.0. 1H NMR and 13C NMR spectra are in
agreement with the literature data.22
4.3.14. 5,7-Dimethyl-3-(4-chlorophenyl)-2-trifluoromethyl-
1H-indole (5n)
Obtained from enamine 2b (276 mg, 1 mmol) and (2,4-dimethyl-
phenyl)hydrazine (136 mg, 1 mmol). Yield: 220 mg (68%); yellow-
4.3.9. 5-Fluoro-3-(4-chlorphenyl)-2-trifluoromethyl-1H-indole (5i)
Obtained from enamine 2b (276 mg, 1 mmol) and (4-fluoro-
phenyl)hydrazine (126 mg, 1 mmol). Yield: 217 mg (69%); white
green powder; mp 99–101 ꢀC; 1H NMR (400 MHz, CDCl3)
d
2.45 (s,
3H, CH3), 2.48 (s, 3H, CH3), 7.07 (s, 1H, Ind), 7.27 (s, 1H, Ind), 7.50 (s,
4H, Ar), 8.34 (br s,1H, NH, Ind); 19F NMR (282 MHz, CDCl3)
ꢁ56.90;
13C NMR (100 MHz, CDCl3)
16.4 (CH3), 21.4 (CH3), 117.7, 118.6 (q,
crystals; mp 62–63 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.16 (td, J¼9.0,
d
2.1 Hz,1H, Ind), 7.27 (dd,J¼9.4, 2.1 Hz,1H, Ind), 7.41–7.45 (m,1H, Ind),
7.45 (d, J¼8.6 Hz, 2H, Ar), 7.49 (d, J¼8.6 Hz, 2H, Ar), 8.64 (br s,1H, NH,
d
J¼2.9 Hz, C]C–CF3), 120.8, 121.2 (q, J¼36.6 Hz, C–CF3), 121.8 (q,
J¼269.3 Hz, CF3), 127.1, 127.6, 128.7, 131.1, 131.2, 131.4, 133.1, 133.5.
Anal. Calcd for C17H13F3N: C, 63.07; H, 4.05. Found: C, 63.02; H, 4.08.
Ind);19FNMR (282 MHz, CDCl3)
d
ꢁ121.47(td, J¼9.1, 4.3 Hz, F), ꢁ57.14
(CF3); 13C NMR (100 MHz, CDCl3)
d
105.5 (d, J¼23.4 Hz), 112.9 (d,
J¼10.3 Hz), 114.4 (d, J¼26.3 Hz), 118.6 (q, J¼2.9 Hz, C]C–CF3), 121.3
(q, J¼269.3 Hz, CF3), 123.0 (q, J¼36.6 Hz, C–CF3), 127.6 (d, J¼10.3),
133.9, 158.8 (d, J¼237.1 Hz) (Ind), 128.9, 130.2, 131.0, 131.5 (Ar). Anal.
Calcd for C15H8F4N: C, 57.43; H, 2.57. Found: C, 57.38; H, 2.58.
4.4. Synthesis of 1-benzyl-1-(trifluoromethyl)-2,3,4,9-
tetrahydro-1H-b-carbolines 7 and 1-benzyl-6,7-diethoxy-1-
(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolines 11
(general procedure)
4.3.10. 5-Cyano-3-(4-chlorophenyl)-2-trifluoromethyl-
1H-indole (5j)
In a 25 mL round bottomed flask the corresponding b-substituted
Obtained from enamine 2b (276 mg, 1 mmol) and (4-cyano-
phenyl)hydrazine (133 mg, 1 mmol). Yield: 161 mg (50%); brown
ethylamine (1.05 mmol) and the enamine 2 (1 mmol) were dissolved
in CH2Cl2 (3 mL) and CF3COOH was added (0.16 mL, 2 mmol). The
reaction mixture remained at room temperature for 5–7 days (TLC
monitoring), diluted with CH2Cl2 (20–30 mL) and washed with
crystals; mp 198–200 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.44 (d,
J¼8.8 Hz, 2H, Ar), 7.51 (d, J¼8.8 Hz, 2H, Ar), 7.59–7.65 (m, 2H, Ind),

7558
V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 7553–7561
saturated K2CO3 solution in a separating funnel. After drying over
Na2SO4, the volatiles were removed in vacuo and the residue was
purified by column chromatography on silica gel using CH2Cl2 as
eluent.
(q, J¼26.3 Hz, C–CF3), 126.9 (q, J¼287.6 Hz, CF3), 111.3, 115.6, 118.9,
119.8, 123.1, 126.5, 126.9, 136.2 (Ind), 129.2, 129.5, 130.4, 139.1 (Ar),
166.9 (CO2CH3). ESI-MS (m/z): calcd for C21H20F3N2O2 [Mþ]
389.1477, found 389.1474. Anal. Calcd for C21H19F3N2O2: C, 64.94; H,
4.93. Found: C, 65.07; H, 4.69.
4.4.1. 1-(4-Nitrobenzyl)-1-trifluoromethyl-2,3,4,9-tetrahydro-
1H-b
-carboline (7a)
4.4.5. 1-(2-Bromobenzyl)-1-trifluoromethyl-2,3,4,9-tetrahydro-1H-
Obtained from enamine 2a (286 mg, 1 mmol) and tryptamine
b-carboline (7e)
(168 mg,1.05 mmol). Yield: 263 mg (70%); yellow crystals; mp 181–
Obtained from enamine 2e (320 mg, 1 mmol) and tryptamine
183 ꢀC; 1H NMR (400 MHz, CDCl3)
d
1.71 (br s, 1H, CH2CH2NH),
(168 mg, 1.05 mmol). Yield: 249 mg (61%); white powder; mp 142–
2.18–2.31, 2.60–2.69, 2.98–3.07, 3.12–3.22, (all m, 1H, CH2CH2NH),
3.26, 3.48 (both d, J¼13.5 Hz, 1H, CH2Ar), 6.99 (d, J¼8.5 Hz, 2H, Ar),
7.17 (t, J¼7.2 Hz, 1H, Ind), 7.29 (t, J¼7.2 Hz, 1H, Ind), 7.44–7.53 (m,
2H, Ind), 7.97 (d, J¼8.5 Hz, 2H, Ar), 8.15 (br s, 1H, NH, Ind); 19F NMR
144 ꢀC; 1H NMR (400 MHz, CDCl3)
d
2.07 (br s, 1H, CH2CH2NH),
2.23–2.33, 2.85–2.94, 3.08–3.18 (all m, 1H, CH2CH2NH), 2.66 (dt,
J¼15.4, 4.3 Hz, 1H, CH2CH2NH), 3.42, 3.81 (both d, J¼13.9 Hz, 1H,
CH2Ar), 6.48 (dd, J¼7.8, 1.1 Hz, 1H, Ar), 6.92 (td, J¼7.8, 1.1 Hz,1H, Ar),
7.04 (td, J¼7.8, 1.1 Hz, 1H, Ar), 7.19 (td, J¼7.6, 0.8 Hz, 1H, Ind), 7.30
(td, J¼7.6, 1.1 Hz, 1H, Ind), 7.47 (d, J¼7.8 Hz, 1H, Ar), 7.52–7.56 (m,
2H, Ind), 8.15 (br s, 1H, NH, Ind); 19F NMR (282 MHz, CDCl3)
(282 MHz, CDCl3)
d
ꢁ75.61; 13C NMR (100 MHz, CDCl3)
d 21.8
(CH2CH2NH), 40.3, 40.6 (CH2CH2NH, CH2Ar), 60.2 (q, J¼25.6 Hz, C–
CF3), 126.9 (q, J¼288.3 Hz, CF3),111.3,115.8,119.0,120.1,123.3, 126.4,
126.5, 136.2 (Ind), 123.1, 131.2, 141.8, 147.2 (Ar). ESI-MS (m/z): calcd
for C19H17F3N3O2 [Mþ] 376.1273, found 376.1272. Anal. Calcd for
C19H16F3N3O2: C, 60.80; H, 4.30. Found: C, 60.81; H, 4.24.
d
ꢁ75.48; 13C NMR (100 MHz, CDCl3)
d 21.8 (CH2CH2NH), 39.3, 40.3
(CH2CH2NH, CH2Ar), 61.0 (q, J¼26.4 Hz, C–CF3),127.0 (q, J¼286.9 Hz,
CF3), 111.3, 115.9, 118.9, 119.8, 123.0, 126.4, 126.6, 136.2 (Ind), 126.9,
127.3, 128.8, 131.6, 132.8, 133.9 (Ar). ESI-MS (m/z): calcd for
C19H17BrF3N2 [Mþ] 409.0527, found 409.0522. Anal. Calcd for
C19H16BrF3N2: C, 55.76; H, 3.94. Found: C, 55.59; H, 3.84.
4.4.2. 1-(4-Chlorobenzyl)-1-trifluoromethyl-2,3,4,9-tetrahydro-
1H-b-carboline (7b)
Obtained from enamine 2b (276 mg, 1 mmol) and tryptamine
(168 mg, 1.05 mmol). Yield: 230 mg (63%); yellow powder; mp
4.4.6. 1-(2-Nitrobenzyl)-1-trifluoromethyl-2,3,4,9-tetrahydro-1H-
169–172 ꢀC; 1H NMR (400 MHz, CDCl3)
d
2.21–2.31, 2.63–2.70,
b-carboline (7f)
3.04–3.09, 3.11–3.16, (all m, 1H, CH2CH2NH), 3.16, 3.41 (both d,
J¼13.9 Hz, 1H, CH2Ar), 6.71 (d, J¼8.3 Hz, 2H, Ar), 7.10 (d, J¼8.3 Hz,
2H, Ar), 7.20 (t, J¼7.6 Hz, 1H, Ind), 7.31 (t, J¼7.6 Hz, 1H, Ind), 7.44–
7.50 (m, 2H, Ind), 8.43 (br s,1H, NH, Ind); 19F NMR (282 MHz, CDCl3)
Obtained from enamine 2f (286 mg, 1 mmol) and tryptamine
(168 mg,1.05 mmol). Yield: 248 mg (66%); yellow powder; mp 116–
118 ꢀC; 1H NMR (400 MHz, CDCl3)
d
2.17–2.26, 2.89–2.97, 3.10–3.18
(all m, 1H, CH2CH2NH), 2.56 (dt, J¼14.9, 3.4 Hz, 1H, CH2CH2NH),
3.48, 3.97 (both d, J¼13.6 Hz, 1H, CH2Ar), 6.81 (dd, J¼7.8, 1.0 Hz, 1H,
Ar), 7.10–7.16 (m, 2H, Ind), 7.22–7.29 (m, 2H, Ar), 7.44 (d, J¼8.6 Hz,
2H, Ind), 7.76 (dd, J¼8.1, 1.3 Hz, 1H, Ar), 8.16 (br s, 1H, NH, Ind); 19F
d
ꢁ75.45; 13C NMR (100 MHz, CDCl3)
d 22.0 (CH2CH2NH), 39.6, 40.4
(CH2CH2NH, CH2Ar), 59.9 (q, J¼26.4 Hz, C–CF3), 127.0 (q, J¼287.6 Hz,
CF3), 111.4, 115.6, 119.0, 119.8, 123.1, 126.6, 127.0, 136.2 (Ind), 128.5,
131.6, 132.0, 133.4 (Ar). ESI-MS (m/z): calcd for C19H17ClF3N2 [Mþ]
365.1032, found 365.1027. Anal. Calcd for C19H16ClF3N2: C, 62.56; H,
4.42. Found: C, 63.81; H, 4.24.
NMR (282 MHz, CDCl3)
d
ꢁ75.90; 13C NMR (100 MHz, CDCl3)
d 21.3
(CH2CH2NH), 36.3, 40.0 (CH2CH2NH, CH2Ar), 61.2 (q, J¼25.6 Hz, C–
CF3), 127.3 (q, J¼287.1 Hz, CF3), 111.3, 115.7, 118.7, 119.8, 122.9, 126.0,
126.4, 136.3 (Ind), 124.2, 127.8, 129.3, 131.9, 132.7, 151.3 (Ar). ESI-MS
(m/z): calcd for C19H17F3N3O2 [Mþ] 376.1273, found 376.1267. Anal.
Calcd for C19H16F3N3O2: C, 60.80; H, 4.30. Found: C, 60.91; H, 4.14.
4.4.3. 1-Benzyl-1-trifluoromethyl-2,3,4,9-tetrahydro-
1H-b-carboline (7c)
Obtained from enamine 2c (241 mg, 1 mmol) and tryptamine
(168 mg, 1.05 mmol). Yield: 198 mg (60%); grey powder; mp 117–
4.4.7. 1-(3-Nitrobenzyl)-1-trifluoromethyl-2,3,4,9-tetrahydro-1H-
118 ꢀC; 1H NMR (400 MHz, CDCl3)
d
1.75 (br s,1H, CH2CH2NH), 2.18–
b-carboline (7g)
2.29, 3.03–3.11, 3.13–3.20 (all m, 1H, CH2CH2NH), 2.78 (dt, J¼15.2,
3.7 Hz, 1H, CH2CH2NH), 3.23, 3.48 (both d, J¼13.6 Hz, 1H, CH2Ar),
6.82 (d, J¼7.1 Hz, 2H, Ar), 7.15–7.28 (m, 4H, Ind, Ar), 7.35 (td, J¼7.9,
1.0 Hz,1H, Ind), 7.50 (d, J¼7.9 Hz,1H, Ind), 7.58 (d, J¼7.9 Hz,1H, Ind),
Obtained from enamine 2g (286 mg, 1 mmol) and tryptamine
(168 mg, 1.05 mmol). Yield: 255 mg (68%); yellow powder; mp
167–168 ꢀC; 1H NMR (400 MHz, CDCl3)
d
1.80 (br s, 1H, CH2CH2NH),
2.20–2.30, 3.03–3.11, 3.15–3.22 (all m, 1H, CH2CH2NH), 2.65 (dt,
J¼15.2, 3.5 Hz, 1H, CH2CH2NH), 3.25, 3.47 (both d, J¼13.9 Hz, 1H,
CH2Ar), 7.05 (d, J¼8.0 Hz, 1H, Ar), 7.16 (t, J¼7.8 Hz, 1H, Ind), 7.24 (t,
J¼8.0 Hz, 1H, Ar), 7.28 (t, J¼7.8 Hz, 1H, Ind), 7.47 (t, J¼7.8 Hz, 2H,
Ind), 7.89 (d, J¼1.4 Hz, 1H, Ar), 8.03 (dd, J¼8.0, 1.4 Hz, 1H, Ar), 8.22
8.20 (br s, 1H, NH, Ind); 19F NMR (282 MHz, CDCl3)
d
ꢁ75.61; 13C
NMR (100 MHz, CDCl3)
d 22.0 (CH2CH2NH), 40.4, 40.5 (CH2CH2NH,
CH2Ar), 60.0 (q, J¼26.3 Hz, C–CF3), 127.1 (q, J¼286.9 Hz, CF3), 111.4,
115.6, 118.9, 119.8, 123.0, 126.7, 136.2 (Ind), 127.5, 128.5, 130.3, 133.4
(Ar). ESI-MS (m/z): calcd for C19H18F3N2 [Mþ] 331.1422, found
331.1417. Anal. Calcd for C19H17F3N2: C, 69.08; H, 5.19. Found: C,
68.98; H, 5.13.
(br s, 1H, NH, Ind); 19F NMR (282 MHz, CDCl3)
d
ꢁ75.11; 13C NMR
(100 MHz, CDCl3)
d 21.8 (CH2CH2NH), 40.3, 40.4 (CH2CH2NH,
CH2Ar), 60.2 (q, J¼25.6 Hz, C–CF3), 127.5 (q, J¼287.3 Hz, CF3), 111.3,
115.8, 118.8, 120.0, 123.2, 126.3, 126.4, 136.2 (Ind), 122.3, 125.5,
128.9, 136.3, 147.8 (Ar). ESI-MS (m/z): calcd for C19H17F3N3O2 [Mþ]
376.1273, found 376.1267. Anal. Calcd for C19H16F3N3O2: C, 60.80; H,
4.30. Found: C, 60.71; H, 4.20.
4.4.4. Methyl 4-([1-trifluoromethyl-2,3,4,9-tetrahydro-1H-
b-carboline-1-yl]methyl)benzoate (7d)
Obtained from enamine 2d (299 mg, 1 mmol) and tryptamine
(168 mg, 1.05 mmol). Yield: 272 mg (70%); white powder; mp 87–
89 ꢀC; 1H NMR (400 MHz, CDCl3)
d
1.83 (br s, 1H, CH2CH2NH), 2.18–
4.4.8. 1-(4-Methoxybenzyl)-1-trifluoromethyl-2,3,4,9-tetrahydro-
2.27, 2.95–3.05, 3.10–3.19 (all m, 1H, CH2CH2NH), 2.65 (dt, J¼15.2,
3.4 Hz, 1H, CH2CH2NH), 3.22, 3.49 (both d, J¼13.5 Hz, 1H, CH2Ar),
3.89 (s, 3H, CO2CH3), 6.88 (d, J¼8.1 Hz, 2H, Ar), 7.19 (t, J¼7.7 Hz, 1H,
Ind), 7.30 (t, J¼7.7 Hz, 1H, Ind), 7.47 (d, J¼7.7 Hz, 1H, Ind), 7.52 (d,
J¼7.7 Hz, 1H, Ind), 7.82 (d, J¼8.1 Hz, 2H, Ar), 8.58 (br s, 1H, NH, Ind);
1H-b-carboline (7h)
Obtained from enamine 2h (271 mg, 1 mmol) and tryptamine
(168 mg, 1.05 mmol). Yield: 240 mg (67%); white powder; mp 126–
127 ꢀC; 1H NMR (400 MHz, CDCl3)
d 1.74 (br s, 1H, CH2CH2NH),
2.20–2.31, 3.05–3.13, 3.14–3.22 (all m, 1H, CH2CH2NH), 2.69 (dt,
J¼15.2, 3.4 Hz, 1H, CH2CH2NH), 3.17, 3.43 (both d, J¼13.9 Hz, 1H,
CH2Ar), 3.75 (s, 3H, OCH3), 6.70 (s, 4H, Ar), 7.24 (td, J¼7.8, 0.8 Hz,1H,
19F NMR (282 MHz, CDCl3)
d
ꢁ75.38; 13C NMR (100 MHz, CDCl3)
d
21.9 (CH2CH2NH), 40.4 (CH2CH2NH, CH2Ar), 52.1 (CO2CH3), 60.0

V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 7553–7561
7559
Ind), 7.35 (td, 1H, Ind, J¼7.8, 1.1 Hz), 7.49 (d, 1H, Ind, J¼7.8 Hz), 7.59
(d, 1H, Ind, J¼7.8 Hz), 8.30 (br s, 1H, NH, Ind); 19F NMR (282 MHz,
1 mmol) and HOAc (3 mL) were stirred until the enamine dis-
appeared (about 1 h, TLC monitoring). The reaction mixture was
refluxed for 3 h and HOAc was evaporated in vacuo. The residue
was diluted with CH2Cl2 (30 mL) and washed with saturated K2CO3
solution. After drying over Na2SO4, the volatiles were removed in
vacuo and the residue was purified by column chromatography on
silica gel using CH2Cl2 as eluent giving a 67:33 mixture of di-
astereomers. Yield: 181 mg (43%); colorless solid; IR (Nujol) 1360,
1540 (NO2), 1670 (C]C) cmꢁ1. Major diastereomer: 1H NMR
CDCl3)
d
ꢁ75.53; 13C NMR (100 MHz, CDCl3)
d 22.1 (CH2CH2NH),
39.4, 40.6 (CH2CH2NH, CH2Ar), 55.2 (OCH3), 55.9 (q, J¼25.6 Hz, C–
CF3), 127.1 (q, J¼286.9 Hz, CF3), 111.4, 115.6, 118.9, 119.8, 122.9, 126.7,
127.7, 136.2 (Ind), 113.9, 125.2, 131.4, 159.0 (Ar). ESI-MS (m/z): calcd
for C20H20F3N2O [Mþ] 361.1528, found 361.1525. Anal. Calcd for
C20H19F3N2O: C, 66.66; H, 5.31. Found: C, 66.90; H, 5.19.
4.4.9. 6-n-Butyl-1-(4-chlorobenzyl)-1-trifluoromethyl-2,3,4,9-
(400 MHz, CDCl3) d 2.73–2.83, 2.97–3.07, 3.08–3.13 (all m, 1H,
tetrahydro-1H-
b
-carboline (7i)
CHCH2NH), 3.24, 3.45 (both d, J¼13.9 Hz, 1H, CH2Ar), 3.80 (s, 3H,
CO2CH3), 6.91 (d, J¼8.2 Hz, 2H, Ar), 7.16 (d, J¼8.2 Hz, 2H, Ar), 7.19 (t,
J¼7.5 Hz, 1H, Ind), 7.29 (t, J¼7.5 Hz, 1H, Ind), 7.42–7.49 (m, 1H, Ind),
7.52–7.58 (m, 1H, Ind), 8.26 (br s, 1H, NH, Ind); 13C NMR (100 MHz,
Obtained from enamine 2b (276 mg, 1 mmol) and 2-(5-butyl-
1H-indol-3-yl)ethylamine (227 mg, 1.05 mmol). Yield: 316 mg
(75%); brown viscous oil; 1H NMR (400 MHz, CDCl3)
d 1.02 (t,
J¼7.3 Hz, 3H, CH2CH2CH2CH3), 1.35 (br s, 1H, CH2CH2NH), 1.41–1.53,
1.69–1.78 (both m, 2H, CH2CH2CH2CH3), 2.67 (dt, J¼15.4, 3.4 Hz, 1H,
CH2CH2NH), 2.79 (t, J¼7.7 Hz, 2H, CH2CH2CH2CH3), 2.22–2.31, 3.02–
3.08, 3.12–3.20, (all m, 1H, CH2CH2NH), 3.16, 3.41 (both d, J¼13.8 Hz,
1H, CH2Ar), 6.74 (d, J¼8.3 Hz, 2H, Ar), 7.14 (d, J¼8.3 Hz, 2H, Ar), 7.17
(d, J¼7.6 Hz, 1H, Ind), 7.35 (s, 1H, Ind), 7.39 (d, J¼8.3 Hz, 1H, Ind),
CDCl3) d 24.3 (CHCH2NH), 38.7, 40.7 (CHCH2NH, CH2Ar), 52.5
(CO2CH3), 61.5 (q, J¼26.3 Hz, C–CF3), 125.8 (q, J¼285.4 Hz, CF3),
111.4, 113.1, 118.8, 120.1, 123.2, 126.2, 127.2, 136.6 (Ind), 128.7, 131.5,
132.6, 135.5 (Ar), 172.1 (CO2CH3). Minor diastereomer: 1H NMR
(CDCl3)
d 2.05–2.14, 3.95–4.02 (both m, 1H, CHCH2NH), 3.17, 3.37
(both d, J¼13.7 Hz, 1H, CH2Ar), 6.72 (d, J¼8.3 Hz, 2H, Ar), 7.16 (d,
8.14 (br s, 1H, NH, Ind); 19F NMR (282 MHz, CDCl3)
d
ꢁ75.73; 13C
J¼8.3 Hz, 2H, Ar), 8.36 (br s, 1H, NH, Ind); 13C NMR (CDCl3)
d 23.7
NMR (100 MHz, CDCl3)
d
14.1 (CH2CH2CH2CH3), 22.1 (CH2CH2NH),
(CHCH2NH), 38.3, 39.7 (CHCH2NH, CH2Ar), 52.3 (CO2CH3), 57.9 (q,
J¼27.1 Hz, C–CF3), 114.2, 118.7, 120.0, 123.3, 126.1, 126.6, 136.4 (Ind),
128.8, 131.6, 132.5, 133.4 (Ar), 172.3 (CO2CH3), the other signals are
identical to those of the major diastereomer. Calcd for
C21H18ClF3N2O2: C, 59.65; H, 4.29. Found: C, 59.71; H, 4.24.
22.6 (CH2CH2CH2CH3), 34.5 (CH2CH2CH2CH3), 35.9 (CH2CH2CH2
CH3), 39.8, 40.5 (CH2CH2NH, CH2Ar), 60.0 (q, J¼26.4 Hz, C–CF3),
127.0 (q, J¼287.6 Hz, CF3), 111.0, 115.4, 118.0, 124.1, 126.8, 127.2,
134.5, 134.8 (Ind), 128.6, 131.7, 132.2, 133.5 (Ar). ESI-MS (m/z): calcd
for C23H25ClF3N2 [Mþ] 421.1658, found 421.1653. Anal. Calcd for
C23H24ClF3N2: C, 65.63; H, 5.75. Found: C, 65.54; H, 5.86.
4.6. Synthesis of 1-trifluoromethyl-1,2,3,4-tetrahydro-
pyrrolo[1,2-a]pyrazines 13 (general procedure)
4.4.10. 6,7-Diethoxy-1-(4-nitrobenzyl)-1-trifluoromethyl-1,2,3,4-
tetrahydroisoquinoline (11a)
In a 25 mL round bottomed flask 2-(1H-pyrrol-1-yl)ethylamine
12 (0.12 g, 1.05 mmol), the corresponding enamine 2 (1 mmol) and
HOAc were stirred at room temperature for 5 days (TLC monitor-
ing). HOAc was removed in vacuo, the residue was diluted with
CH2Cl2 (30 mL) and washed with saturated K2CO3 solution. After
drying over Na2SO4, the volatiles were removed in vacuo and the
residue was purified by column chromatography on silica gel using
CH2Cl2 as eluent.
Obtained from enamine 2a (286 mg, 1 mmol) and 2-(3,4-
diethoxyphenyl)ethylamine (220 mg, 1.05 mmol). Yield: 181 mg
(54%); viscous yellow oil; 1H NMR (400 MHz, CDCl3)
d 1.46, 1.48
(both t, J¼7.0 Hz, 3H, OCH2CH3), 1.90 (br s, 1H, CH2CH2NH), 2.32–
2.41, 2.45–2.54, 2.83–2.92, 3.09–3.16 (all m, 1H, CH2CH2NH), 3.18,
3.46 (both d, J¼13.7 Hz, 1H, CH2Ar), 4.06, 4.14 (both q, J¼7.0 Hz, 2H,
OCH2CH3), 6.52 (s, 1H, Ar), 7.10 (s, 1H, Ar), 7.16 (d, J¼8.7 Hz, 2H, 4-
NO2C6H4–), 7.99 (d, J¼8.7 Hz, 2H, 4-NO2C6H4–); 13C NMR (100 MHz,
CDCl3)
d
14.8, 14.9 (both OCH2CH3), 29.7 (CH2CH2NH), 39.4, 42.2
4.6.1. 1-(4-Nitrobenzyl)-1-trifluoromethyl-1,2,3,4-
(CH2CH2NH, CH2Ar), 61.8 (q, J¼24.4 Hz, C–CF3), 64.2, 65.3 (both
OCH2CH3), 127.5 (q, J¼290.6 Hz, CF3), 122.8, 131.6, 143.1, 146.7 (4-
NO2C6H4–), 113.3, 113.4, 121.9, 131.1, 146.9, 148.9 (Ar). Anal. Calcd for
C21H23F3N2O4: C, 59.43; H, 5.46. Found: C, 59.57; H, 5.24.
tetrahydropyrrolo[1,2-a]pyrazine (13a)
Obtained from enamine 2a (286 mg, 1 mmol). Yield: 221 mg
(68%); red crystals; mp 110.1–111.5 ꢀC; IR (Nujol) 1360, 1540 (NO2),
1670 (C]C) cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.85 (br s, 1H,
CH2CH2NH), 2.87–2.95, 3.22–3.26, 3.27–3.36, 3.73–3.80 (all m, 1H,
CH2CH2NH), 3.17, 3.44 (both d, J¼13.1 Hz, 1H, CH2Ar), 6.21–6.25,
6.33–6.37, 6.54–6.57 (all m, 1H, pyrrolyl), 7.14 (d, J¼8.7 Hz, 2H, Ar),
4.4.11. 6,7-Diethoxy-1-(4-chlorobenzyl)-1-trifluoromethyl-1,2,3,4-
tetrahydroisoquinoline (11b)
Obtained from enamine 2b (276 mg, 1 mmol) and 2-(3,4-
diethoxyphenyl)ethylamine (220 mg, 1.05 mmol). Yield: 157 mg
8.03 (d, J¼8.7 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3)
d
ꢁ77.49; 13
C
NMR (100 MHz, CDCl3)
d 40.2, 42.7, 45.1 (CH2CH2NH, CH2Ar), 60.8
(48%); viscous colorless oil; 1H NMR (400 MHz, CDCl3)
d
1.46–1.52
(q, J¼26.4 Hz, C–CF3), 126.7 (q, J¼287.6 Hz, CF3), 107.2, 108.0, 120.6,
121.7 (pyrrolyl), 122.9, 131.7, 142.9, 147.1 (Ar). ESI-MS (m/z): calcd
for C15H15F3N3O2 [Mþ] 326.1116, found 326.1116. Anal. Calcd for
C15H14F3N3O2: C, 55.39; H, 4.34. Found: C, 55.37; H, 4.16.
(m, 6H, 2 ꢀCH2CH3), 1.68 (br s, 1H, CH2CH2NH), 2.28–2.38, 2.48–
2.56, 2.80–2.88, 3.04–3.11 (all m, 1H, CH2CH2NH), 3.08, 3.36 (both d,
J¼13.8 Hz, 1H, CH2Ar), 4.09, 4.15 (both q, J¼7.0 Hz, 2H, OCH2CH3),
6.54 (s,1H, Ar), 6.88 (d, J¼8.3 Hz, 2H, 4-ClC6H4–), 7.11 (s,1H, Ar), 7.13
(d, J¼8.3 Hz, 2H, 4-ClC6H4–), 13C NMR (100 MHz, CDCl3)
d
14.8, 14.9
4.6.2. 1-(4-Chlorobenzyl)-1-trifluoromethyl-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazine (13b)
(both OCH2CH3), 29.7 (CH2CH2NH), 39.5, 41.6 (CH2CH2NH, CH2Ar),
61.6 (q, J¼24.2 Hz, C–CF3), 64.2, 65.2 (both OCH2CH3), 127.5 (q,
J¼288.4 Hz, CF3), 128.2, 132.0, 133.3, 139.3 (4-ClC6H4–), 113.3, 114.1,
122.8, 131.2, 146.6, 148.6 (Ar). Anal. Calcd for C21H23ClF3NO2: C,
60.94; H, 5.60. Found: C, 60.71; H, 5.74.
Obtained from enamine 2b (276 mg, 1 mmol). Yield: 220 mg
(70%); pink powder; mp 105–107 ꢀC; 1H NMR (400 MHz, CDCl3)
d
1.73 (br s, 1H, CH2CH2NH), 2.86–2.93, 3.17–3.25, 3.26–3.35, 3.73–
3.79 (all m, 1H, CH2CH2NH), 3.09, 3.39 (both d, J¼13.5 Hz, 1H,
CH2Ar), 6.26–6.30, 6.36–6.40, 6.58–6.61 (all m, 1H, pyrrolyl), 6.87
(d, J¼8.4 Hz, 2H, Ar), 7.20 (d, J¼8.4 Hz, 2H, Ar); 19F NMR (282 MHz,
4.5. Methyl 1-(4-chlorobenzyl)-1-trifluoromethyl-2,3,4,9-
tetrahydro-1H-b-carboline-3-carboxylate (9)
CDCl3)
d
ꢁ77.54; 13C NMR (100 MHz, CDCl3)
d 40.4, 42.2, 45.0
(CH2CH2NH, CH2Ar), 60.5 (q, J¼26.3 Hz, C–CF3),127.1 (q, J¼286.9 Hz,
CF3), 107.2, 108.0, 120.4, 122.3 (pyrrolyl), 128.4, 131.9, 133.1, 133.3
(Ar). ESI-MS (m/z): calcd for C15H14ClF3N2 [Mþ] 315.0876, found
In a 25 mL round bottomed flask a mixture of methyl
L-trypto-
phanate hydrochloride (0.28 g, 1.05 mmol), enamine 2b (276 mg,

7560
V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 7553–7561
315.0870. Anal. Calcd for C15H13ClF3N2: C, 57.43; H, 4.18. Found: C,
57.61; H, 4.24.
4.8.3. 4-Benzyl-4-trifluoromethyl-4,5,6,7-tetrahydro-3H-
imidazo[4,5-c]pyridine (17c)
Obtained from enamine 2c (241 mg, 1 mmol). Yield: 216 mg
4.7. 7-(4-Chlorobenzyl)-7-trifluoromethyl-4,5,6,7-
(77%); viscous brown oil; 1H NMR (400 MHz, CDCl3)
d 1.81 (br s, 1H,
tetrahydrothieno[2,3-c]pyridine (15)
CH2CH2NH), 1.95–2.06, 2.56–2.64 (both m, 1H, CH2CH2NH), 2.86–
3.01 (m, 2H, CH2CH2NH), 3.19, 3.56 (both d, J¼14.3 Hz, 1H, CH2Ar),
6.69–6.77 (m, 2H, Ar), 7.17–7.26 (m, 3H, Ar), 7.86 (s, 1H, imidazolyl);
In a 25 mL round bottomed flask 2-thien-3-ylethylamine 14
(0.13 g, 1.05 mmol), enamine 2b (276 mg, 1 mmol) and HOAc were
stirred at room temperature for 2 days (TLC monitoring). HOAc was
removed in vacuo, the residue was diluted with CH2Cl2 (30 mL) and
washed with saturated K2CO3 solution. Afterdryingover Na2SO4, the
volatiles were removed in vacuo and the residue was purified by
column chromatography on silica gel using CH2Cl2 as eluent. Yield:
179 mg (54%); white powder; mp 72.9–75.2 ꢀC; 1H NMR (400 MHz,
19F NMR (282 MHz, CDCl3)
d
ꢁ75.78; 13C NMR (100 MHz, CDCl3)
d
21.6 (CH2CH2NH), 37.3, 40.9 (CH2CH2NH, CH2Ar), 73.8 (q,
J¼28.6 Hz, C–CF3), 124.8 (q, J¼287.6 Hz, CF3), 128.3, 131.0, 133.9
(imidazolyl), 127.0, 128.4, 129.1, 130.2 (Ar). ESI-MS (m/z): calcd for
C14H15F3N3 [Mþ] 282.1218, found 282.1216. Anal. Calcd for
C14H14F3N3: C, 59.78; H, 5.02. Found: C, 60.01; H, 5.12.
CDCl3)
d
1.70 (br s, 1H, CH2CH2NH), 2.04–2.15, 2.91–2.98, 3.00–3.10
4.8.4. Methyl 4-[(4-trifluoromethyl-4,5,6,7-tetrahydro-3H-
imidazo[4,5-c]pyridine-4-yl)methyl]benzoate (17d)
(all m,1H, CH2CH2NH), 2.51 (dt, J¼15.9, 2.9 Hz,1H, CH2CH2NH), 3.14,
3.31 (both d, J¼13.6 Hz,1H, CH2Ar), 6.78 (d, J¼5.1 Hz,1H, Th), 6.84 (d,
J¼8.3 Hz, 2H, Ar), 7.17 (d, J¼8.3 Hz, 2H, Ar), 7.32 (d, J¼5.1 Hz,1H, Th);
Obtained from enamine 2d (299 mg, 1 mmol). Yield: 149 mg
(44%); white powder; mp 153–154 ꢀC; 1H NMR (400 MHz, CDCl3)
19F NMR (282 MHz, CDCl3)
d
ꢁ76.07; 13C NMR (100 MHz, CDCl3)
d 1.72 (br s, 1H, CH2CH2NH), 2.11–2.21, 2.38–2.46, 2.83–2.92, 3.05–
d
26.5 (CH2CH2NH), 40.0, 42.5 (CH2CH2NH, CH2Ar), 61.9 (q, J¼26.4
3.16 (all m, 1H, CH2CH2NH), 3.09, 3.57 (both d, J¼13.1 Hz, 1H,
CH2Ar), 3.86 (s, 3H, CO2CH3), 6.95 (d, J¼8.2 Hz, 2H, Ar), 7.62 (s, 1H,
imidazolyl), 7.80 (d, J¼8.2 Hz, 2H, Ar), 19F NMR (282 MHz, CDCl3)
Hz, C–CF3), 126.6 (q, J¼286.9 Hz, CF3), 125.0, 127.3, 129.5, 140.3 (Th),
128.4, 131.7, 132.4, 133.4 (Ar). ESI-MS (m/z): calcd for C15H14ClF3NS
[Mþ] 332.0488, found 332.0482. Anal. Calcd for C15H13ClF3NS: C,
54.30; H, 3.95. Found: C, 54.53; H, 4.16.
d
ꢁ75.75; 13C NMR (100 MHz, CDCl3)
d 22.6 (CH2CH2NH), 39.8
(CH2CH2NH, CH2Ar), 52.1 (CO2CH3), 60.5 (q, J¼25.6 Hz, C–CF3),127.0
(q, J¼287.6 Hz, CF3), 128.6, 129.3, 134.3 (imidazolyl), 128.8, 129.1,
130.6, 140.3 (Ar), 167.1 (CO2CH3). ESI-MS (m/z): calcd for
C16H17F3N3O2 [Mþ] 340.1273, found 340.1269. Anal. Calcd for
C16H16F3N3O2: C, 56.64; H, 4.75. Found: C, 56.28; H, 4.56.
4.8. Synthesis of 4-trifluoromethyl-4,5,6,7-tetrahydro-3H-
imidazo[4,5-c]pyridines 17 (general procedure)
In a 25 mL round bottomed flask a mixture of histamine dihy-
drochloride 16 (0.19 g, 1.05 mmol), the corresponding enamine 2
(1 mmol) and EtOH (5 mL) were refluxed until the enamine dis-
appeared (about 3 h, TLC monitoring). A solution of KOH (0.12 g,
2.1 mmol) in EtOH (5 mL) was added in one portion and the re-
action mixture was refluxed for another 15–20 h. EtOH was evap-
orated in vacuo, the residue was diluted with CH2Cl2 (30 mL) and
washed with saturated K2CO3 solution. After drying over Na2SO4,
the volatiles were removed in vacuo and the residue was purified
by column chromatography on silica gel using a mixture CH2Cl2/
MeOH 30:1 as eluent.
4.8.5. 4-(4-Methoxybenzyl)-4-trifluoromethyl-4,5,6,7-tetrahydro-
3H-imidazo[4,5-c]pyridine (17h)
Obtained from enamine 2h (271 mg, 1 mmol). Yield: 140 mg
(45%); brown-yellow powder; mp 114–117 ꢀC; 1H NMR (400 MHz,
CDCl3)
d 2.06–2.18, 2.37–2.45, 2.87–2.95, 3.04–3.12 (all m, 1H,
CH2CH2NH), 2.99, 3.48 (both d, J¼13.6 Hz, 1H, CH2Ar), 3.71 (s, 3H,
CH3O), 6.68 (d, J¼8.7 Hz, 2H, Ar), 6.73 (d, J¼8.7 Hz, 2H, Ar), 7.63 (s,
1H, imidazolyl); 19F NMR (282 MHz, CDCl3)
d
ꢁ75.82; 13C NMR
(100 MHz, CDCl3)
d 22.8 (CH2CH2NH), 38.6, 39.9 (CH2CH2NH,
CH2Ar), 55.1 (CH3O), 60.1 (q, J¼26.4 Hz, C–CF3), 129.9 (q,
J¼285.4 Hz, CF3), 127.8, 130.3, 134.2 (imidazolyl), 113.7, 126.0, 131.4,
158.7 (Ar). ESI-MS (m/z): calcd for C15H17F3N3O [Mþ] 312.1324,
found 312.1318. Anal. Calcd for C15H16F3N3O: C, 57.87; H, 5.18.
Found: C, 57.98; H, 5.11.
4.8.1. 4-(4-Nitrobenzyl)-4-trifluoromethyl-4,5,6,7-tetrahydro-3H-
imidazo[4,5-c]pyridine (17a)
Obtained from enamine 2a (286 mg, 1 mmol). Yield: 215 mg
(66%); viscous brown oil; IR (Nujol) 1360, 1540 (NO2), 1670
(C]C) cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.15–2.27, 2.40–2.48,
Acknowledgements
2.88–2.96, 3.14–3.21 (all m, 1H, CH2CH2NH), 3.08, 3.55 (both d,
J¼13.3 Hz, 1H, CH2Ar), 7.08 (d, J¼8.8 Hz, 2H, Ar), 7.58 (s, 1H, imi-
This project was supported by the Deutsche For-
schungsgemeinschaft (DFG) through grant Gz: 436 RUS 113/858/0-1
and the Russian Foundation for Basic Research (grants no. 08-03-
00736-a, RFBR-DFG 07-03-91562-NNIO_a).
dazolyl), 7.92 (d, J¼8.8 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3)
d 22.3
(CH2CH2NH), 39.6, 39.7 (CH2CH2NH, CH2Ar), 60.7 (q, J¼25.6 Hz, C–
CF3), 127.0 (q, J¼289.1 Hz, CF3), 128.2, 129.2, 134.3 (imidazolyl),
122.7,131.5, 143.2, 146.8 (Ar). Anal. Calcd for C14H13F3N4O2: C, 51.54;
H, 4.02. Found: C, 51.71; H, 4.14.
References and notes
4.8.2. 4-(4-Chlorobenzyl)-4-trifluoromethyl-4,5,6,7-tetrahydro-3H-
imidazo[4,5-c]pyridine (17b)
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Obtained from enamine 2b (276 mg, 1 mmol). Yield: 171 mg
(54%); viscous brown oil; 1H NMR (400 MHz, CDCl3)
d 1.72 (br s, 1H,
CH2CH2NH), 2.01–2.17, 2.61–2.69 (bothm,1H, CH2CH2NH), 2.92–3.09
(m, 2H, CH2CH2NH), 3.19, 3.55 (both d, J¼14.3 Hz,1H, CH2Ar), 6.67 (d,
J¼8.3 Hz, 2H, Ar), 6.78 (s, 1H, imidazolyl), 7.20 (d, J¼8.3 Hz, 2H, Ar),
7.84 (br s, 1H, NH, imidazolyl); 19F NMR (282 MHz, CDCl3)
d
ꢁ75.70;
13C NMR (100 MHz, CDCl3)
d 21.7 (CH2CH2NH), 37.3, 40.4 (CH2CH2NH,
CH2Ar), 73.7 (q, J¼29.3 Hz, C–CF3), 124.6 (q, J¼288.4 Hz, CF3), 128.1,
133.7 (imidazolyl),129.3, 129.6, 131.6, 134.5 (Ar). ESI-MS (m/z): calcd
for C14H14ClF3N3 [Mþ] 316.0828, found 316.0823. Anal. Calcd for
C14H13ClF3N3: C, 53.26; H, 4.15. Found: C, 52.83; H, 4.16.

V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 7553–7561
7561
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