Selective synthesis of α-trifluoromethyl-β-aryl enamines or vinylogous guanidinium salts by treatment of β-halo-β-trifluoromethylstyrenes with secondary amines under different conditions

Article abstract of DOI:10.1016/j.tet.2009.06.048

Unprecedented selective reactions of β-halo-β-trifluoromethylstyrenes with secondary amines under different conditions were discovered. Depending on the electronic properties of the starting styrenes and?the reaction parameters, two pathways were found. W

Full text of DOI:10.1016/j.tet.2009.06.048

Tetrahedron 65 (2009) 6991–7000
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective synthesis of
guanidinium salts by treatment of
a
-trifluoromethyl-
b
-aryl enamines or vinylogous
-trifluoromethylstyrenes with
b
-halo-
b
secondary amines under different conditions
,
b
,
b
Vasiliy M. Muzalevskiy a, Valentine G. Nenajdenko a , Alexander Yu. Rulev , Igor A. Ushakov ,
*
*
Galina V. Romanenko c, Aleksey V. Shastin d, Elizabeth S. Balenkova a, Gu¨nter Haufe e
,
*
a Moscow State University, Department of Chemistry, Leninskie Gory, Moscow 119992, Russia
b A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1, Favorsky Str., Irkutsk 664033, Russia
c The Institute International Tomography Center, Siberian Branch of the Russian Academy of Sciences, 3a, Institutskaya Str., Novosibirsk 630090, Russia
d Institute of Problems of Chemical Physics, Chernogolovka, Moscow Region 142432, Russia
e 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 7 April 2009
Received in revised form 5 June 2009
Accepted 12 June 2009
Available online 18 June 2009
Unprecedented selective reactions of
different conditions were discovered. Depending on the electronic properties of the starting styrenes
and the reaction parameters, two pathways were found. With neat secondary amines a series of
b-halo-b-trifluoromethylstyrenes with secondary amines under
a
-trifluoromethyl-b-aryl enamines were prepared in high yields. In contrast, the reactions of the men-
tioned styrenes with the same amines in polar solvents by substitution of all halogen atoms gave vi-
nylogous guanidinium salts. Possible reaction mechanisms are discussed.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Defluorination
b
-Halo-b-trifluoromethylstyrenes
Secondary amines
Vinylic nucleophilic substitution
a
-Trifluoromethyl-b-aryl enamines
Vinylogous guanidinium salts
1. Introduction
developed using that reaction.5 Also, the ease of
substitution by C-, S- and O-nucleophiles in -chloro- and
-(trifluoromethyl)styrenes or -bromo- -fluorostyrenes was
demonstrated in a series of publications. Treatment of these
compounds with copper cyanide, sodium 4-methylphenylsulfinate,
alkylthiolates, arylthiolates and alkoxides resulted in a number
b
-halogen atom
b
b
b
-bromo-
Organofluorine compounds were intensively investigated in
recent decades.1 The remarkable interest on these compounds is
due to their unique physical and biological properties caused by the
presence of fluorine substituents in the molecules.2 Numerous
publications were dedicated to the elaboration of new synthetic
approaches to fluorine-containing organic compounds, which
resulted in an enormous progress in this field.3
Recently, a new catalytic olefination reaction of aldehydes and
ketones was discovered by our research group.4 This reaction was
found to be a new general approach to construct carbon–carbon
double bonds. A number of convenient and simple methods for the
synthesis of various alkenes including fluorinated ones were
b
b
of novel convenient approaches to
methylacrylonitriles,6 -arylvinyl sulfones,7 trifluoro-
-fluoro-
methyl(vinylsulfides),8 and alkoxy- -(trifluoromethyl)styrenes.9
Having such encouraging results, we decided to continue our
investigations on the synthetic utility of -halo- -(tri-
a-fluoro- and a-trifluoro-
a
b
b
b
b
fluoromethyl)styrenes examining their reactions with N-nucleo-
philes. Initially, secondaryamines were chosen since the substitution
of the b-halogen atom might lead to 1-trifluoromethyl-2-aryl en-
amines. Such compounds have been shown to be promising building
blocks for the synthesis of various new fluorine-containing com-
pounds and natural product analogues.10 Several methods for the
preparation of such enamines have been described in the literature
already. Most important among them are the Wittig reaction
with trifluoroacetamides,11,12 the reaction of amines with
perfluoroalkylketones,13 the addition of amines to trifluromethyl-
* Corresponding authors. Tel.: þ49 251 83 33281; fax: þ49 251 83 39772 (G.H.);
tel.: þ7 495 9392276; fax: þ7 495 9328846 (V.G.N.); tel.: þ7 3952 511429;
fax: þ7 3952 419346 (A.Y.R.).
E-mail addresses: nen@acylium.chem.msu.ru (V.G. Nenajdenko), rulev@irioch.irk.ru
(A.Yu. Rulev), romanenko@tomo.nsc.ru (G.V. Romanenko), shastin@icp.ac.ru (A.V. Shas-
tin), haufe@uni-muenster.de (G. Haufe).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.048

6992
V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 6991–7000
acetylenes,10c the direct trifluoromethylation of pyrrolidinones10d
and nucleophilic substitutions of trifluoromethylated vinyl halides.
The latter method itself provides one of the most general pathways
towards capto-dative alkenes, especially for systems bearing halogen
or another leaving group in gem-position to a strong electron-
withdrawing substituent.14 Accordingly, 1-perfluoroalkyl enamines
were prepared by substitution of fluorine in fluorostyrenes using
lithium alkylamides.15 Generally, this reaction is not stereoselective
and formation of two regioisomers was observed in many cases.
Nevertheless, in some particular alkenes nucleophilic substitution
of the vinylic leaving group with lithium alkylamides proceeded
stereoselective and the enamines 4a and 5–8 were isolated as
Z/E-mixtures (70:30 to 95:5).
The synthetic scope and limitations of the method were in-
vestigated using the most reactive secondary amine, pyrrolidine, as
a model in reactions with a series of styrenes, containing either
electron-withdrawing or electron-donating substituents in the aryl
ring. The reactions of the styrenes 1 and 2 bearing electron-with-
drawing groups proceeded smoothly and within minutes at room
temperature giving the desired enamines 3 regio- and stereo-
selectively in high yields. Although the styrenes 1 and 2 were used
as mixtures of Z/E-isomers (see Table 1 and Refs. 5b and e), the
corresponding enamines 3 were generally obtained as single
Z-isomers. Only in case of the enamines 3f and 3h with ortho-
substituents admixture of the E-isomer was found. The Z/E-ratio
was 92:8 and 88:12, respectively. The configuration of the 1-tri-
fluoromethyl enamines was determined spectroscopically. The
proton decoupled 13C NMR spectra of compounds 3 were recorded
regio- and stereoselectively. Substitution of an ethoxy group in
ethoxy-
-trifluoromethylstyrenes10g and of the chlorine atom in
-chloro-
-trifluoromethylstyrenes16 by treatment with two
b-
b
b
b
equivalents of lithium alkylamides gave the corresponding enamines
in highyields as single regio- and stereoisomers. We considered, that
b-bromostyrenes would be more reactive than b-chlorostyrene.
3
Furthermore, electron withdrawing groups in the aromatic ring
should increase the reactivity and the corresponding enamines
might be available under milder conditions without application of
organometallic reagents.
and the spin–spin coupling constants JH,C between the tri-
fluoromethyl carbon atom and the proton at the double bond were
determined to range between 4.4 and 4.7 Hz. Consequently, this
proton and the trifluoromethyl group are in cis-position and the
compounds have Z-configuration.17 Configurations of both Z- and
E-isomers of compound 3h were confirmed unambiguously by
NOESY experiments (Fig. 1). Additionally, 1H and 13C spectra of
compound 3c are in good agreement with literature data for the
previously described Z-isomer.10g
2. Results and discussion
Initially, we investigated the most reactive styrene 1a, bearing
a nitro group in para-position of the aryl ring. The reaction of an
88:12 Z/E-mixture of 1a with excess of pyrrolidine without solvent
proceeded very fast accompanied by remarkable heat evolution.
The starting material was consumed within a minute and the de-
sired enamine 3a was obtained regio- and stereoselectively as pure
Z-isomer in almost quantitative yield (Scheme 1, Table 1).
NO2
NO2
H
H
H2C
N
CF3
N
H2C
CF3
H
H
H
H
CF3
CF3
NR1R2
i, ii or iii
68-98%
Z-3h
E-3h
X
NOE interaction
Ar
1 X=Cl, 2 X=Br
Ar
3-9
Figure 1. Configurations of Z- and E-isomers of compound 3h according to NOESY.
Scheme 1. Reactions of -chloro- and b-bromo-b-trifluoromethylstyrenes 1 and 2
b
with pyrrolidine. Conditions: (i) 10 equiv HNR1R2, rt (3a–3h); (ii) 10 equiv HNR1R2,
heating in a sealed tube (4a, 5–8); (iii) 7.5 equiv HNR1R2, EtOH, reflux (3a, 9).
We found that the nature of the halogen atom is not important
in case of styrenes with electron-withdrawing groups such as nitro
and methoxycarbonyl functions. High yields of enamines were
observed starting either from chloro-1a, 1g and 1h or bromostyr-
enes 2e. In case of less electron withdrawing halogen substituents
in the aromatic ring the yields dropped dramatically from bromo to
chlorostyrenes (1b and 2b). For the unsubstituted or the 4-methoxy
styrenes 2c and 2d, the reaction rate decreased significantly and
only traces of the desired enamines 3c and 3d were observed
In case of less active secondary amines the reactions proceeded
much slower under the same conditions. For example, piperidine
gave the corresponding enamine 4a only after 3 days of standing at
room temperature. Nevertheless, the reactions with less reactive
secondary amines were successfully performed at heating, giving
the desired enamines 4a and 5–8 as single regioisomers in high
yields (Table 1). However, the reaction was found to be less
Table 1
Synthesis of
a
-trifluoromethyl-b-aryl enamines 3–9
Styrene
Z/E ratioa
Ar
R1–R2
T (ꢀC)
Enamine
Z/E ratioa
Yield (%)
1a
1a
1a
1a
1a
1a
1a
1b
2b
2c
2d
2e
2f
88:12
88:12
88:12
88:12
88:12
88:12
88:12
75:25
89:11
86:14
89:11
83:17
66:34
75:25
83:17
83:17
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
–(CH2)4–
–(CH2)4–
–(CH2)5–
–(CH2)6–
–(CH2)2O(CH2)2–
–(CH2)2NH(CH2)2–
Et
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
n-Pr
rt
3a
3a
4a
5
6
7
100:0
96:4
83:17
96:4
71:29
95:5
88:12
100:0
100:0
d
95
Refluxb
85
69b
89
125
125
125
85
rt
rt
rt
rt
rt
rt
78
84
92
82
31
68
Traces
Traces
85
8
3b
3b
3c
3d
3e
3f
3g
3h
9
4-ClC6H4
Ph
4-MeOC6H4
4-MeCO2C6H4
2-BrC6H4
3-NO2C6H4
2-NO2C6H4
2-NO2C6H4
d
100:0
92:8
100:0
88:12
92:8
75
78
1g
1h
1h
rt
rt
98
Refluxb
53b
Determined by 1H NMR spectroscopy.
The reactions were carried out in ethanol.
a
b

V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 6991–7000
6993
within complex mixtures of other products. However, the Z-con-
figurated enamines 3b–3d were synthesized in high yields by re-
action of the styrenes 1b–1d with two equivalents of lithiated
pyrrolidine (Scheme 2).
The structure of the salt 10b was determined by NMR-spec-
troscopy, mass spectrometry, elemental analysis and was doubt-
lessly confirmed by X-ray analysis (Fig 2).
CF3
Cl
CF3
i - iii
N
Ar
Ar
1b
1c
1d
Ar = 4-ClC6H4
Ar = C6H5
Ar = 4-CH3OC6H5
3b (76%)
3c (67%)
3d (63%)
Scheme 2. Reactions of b-chloro-b-trifluoromethylstyrenes 1 with lithium pyrrolidide.
Conditions: (i) 2 equiv pyrrolidine, 2.2 equiv BuLi, THF, ꢁ78 ꢀC; (ii) ꢁ78 ꢀC to 0 ꢀC, 2 h;
(iii) NH4Cl.
Unexpected results were obtained when the reactions of sty-
renes 1 and 2 with secondary amines were performed in polar
solvents. The most reactive styrene 1a showed dramatic drop of the
reaction rate with pyrrolidine in dry ethanol giving acceptable yield
of 3a only at reflux (Table 1, line 2). This might be attributed to the
formation of hydrogen bonds between ethanol and pyrrolidine and
hence drop of its reactivity. It should also be noted, that the reaction
was less stereoselective in refluxing ethanol providing 3a as a 96:4
mixture of Z- and E-isomers in 69% yield. Much more surprising
results were obtained for less electron deficient styrenes. Refluxing
the styrene 2b with 10 equiv of pyrrolidine in ethanol led to the
E-isomer of the vinylogous guanidinium salt 10b in 86% yield as the
main product (Scheme 3, Table 2). Thus, all halogen atoms were
replaced by the nucleophile. This is another of the quite rare ex-
amples of substitution of all three fluorine atoms of a trifluorometyl
group by a nitrogen nucleophile. While the activation of aliphatic
C–F bonds in saturated compounds by use of transition metals as
reducing agents is well documented,18 only a few papers reported
the substitution of aliphatic C–F bonds by means of the nucleophilic
attack of sulfur-, oxygen- or nitrogen compounds without metal
catalysis.19
Figure 2. X-ray structure of compound 10b.
The analyzed crystal of 10b was found to be a hydrate,
10b$H2O. The pyrrolidine rings have envelope conformation with
0.55–0.60 Å deviation from the plane. Generally, C–N bond lengths
vary between 1.466(4) and 1.494(4) Å, whereas the C(7)–N(7),
C(13)–N(13) and C(13)–N(17) bonds are significantly shorter
(1.338(4)–1.359(4) Å) in 10b. The carbon–carbon bond lengths
C(12)–C(7) and C(12)–C(13) are different, 1.377(4) and 1.445(4) Å,
respectively, but both are between a single and a double bond in-
dicating the conjugated system. Bromide and the water molecules
are connected by hydrogen bonds. Weak van-der-Waals in-
teractions were found between neighboring ions.
The NMR signals of the pyrrolidine ring protons connected to
the double bond are significantly broadened at room temperature
due to hindered rotation of the C–N bond. Low temperature ex-
periments provided a rotation barrier of about 14 kcal/mol. In the
1H and 13C NMR spectra two sets of signals of amino moieties were
found in 2:1 ratio. The coalescence point of their signals lays as low
as approximately 230–240 K. The chemical shifts of 15N atoms in
CF3
X
NR2R1
2R1RN
10 equiv HNR1R2
31-87%
X
Ar NR2R1
Ar
1 X=Cl
2 X=Br
10-17
Scheme 3. Reactions of
b-chloro- and b-bromo-b-trifluoromethylstyrenes 1 and 2
with secondary amines in the presence of solvents.
Table 2
Synthesis of vinylogous guanidinium salts 10–17
Styrene
Ar
R1–R2
Solvent
T (ꢀC)
Time (h)
Product
Yield (%)
2b
2d
1b
1b
1d
1i
4-ClC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-BrC6H4
2-Pyridinyl
4-ClC6H4
4-MeOC6H4
2-BrC6H4
4-BrC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)5–
–(CH2)6–
–(CH2)2O(CH2)2–
–(CH2)2NH(CH2)2–
Et
EtOH
EtOH
EtOH
THF
Neat
EtOH
THF
EtOH
EtOH
Dioxane
EtOH
EtOH
Neat
Neat
EtOH
Neat
Reflux
Reflux
85–88
85–88
85–88
Reflux
85–88
120
120
Reflux
110
110
130
6
6
17
17
16
6
16
16
16
13
13
9
75
75
16
75
10b
10d
11b
11b
11d
11i
11j
12b
12d
12f
13i
12k
14
86
76
19a
74
87
13b
74
1j
2b
2d
2f
66
42
35c
59
39
75
32d
0
1i
2k
2b
2b
2b
2b
130
120
130
15
16
17
66
a
70% of starting material was recovered.
47% of starting material was recovered.
52% of enamine 4f was isolated as a 70:30 mixture of Z- and E-isomers.
b
c
d
Substitution of bromine atom in aryl ring by morpholine was observed.

6994
V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 6991–7000
10b were measured using the 2D HMBC 1H–15N method. For the
nitrogen neighboring the double bond ꢁ258.3 ppm was deter-
mined, while the nitrogen atoms connected to the positively
charged carbon atom are shifted downfield to ꢁ269.4 ppm. Nev-
ertheless, the quite similar chemical shift values of all three nitro-
gen atoms prove the significant charge delocalization.
Although the loss of fluorine is observed in that case, the re-
action is interesting since it provides a novel pathway to vinylogous
guanidinium salts, which were used, for example, for the synthesis
of 1,1,3-tris-(dialkylamino)propadiene derivatives.20 In order to
investigate thoroughly this unusual reaction pathway, we reacted
several styrenes 1 and 2 with pyrrolidine and a number of other
secondary amines both neat and in solvents. In this way a series of
vinylogous guanidinium salts 10–17 was synthesized in moderate
to high yields. Electron deficient as well as electron rich styrenes do
react in this way. The reaction of the p-chlorostyrene 1b with
pyrrolidine proceeded considerably faster in THF providing 11b in
74% yield after 17 h at 85–88 ꢀC, while the reaction in EtOH at
the same temperature gave only 19% of 11b after 17 h. The nature of
It should be noted that both the quantity and the ratio of ste-
reoisomers 3b did not change with time and remained constant
even after heating for several hours. The share of compounds 18b
and 19b in the reaction mixture decreased with time and both
compounds disappeared after reflux. Simultaneously, the relative
amount of the salt 10b increased on the expense of compounds 18b
and 19b. On the other hand compound 3b did not participate in the
formation of the salt 10b. Another proof is the experimental fact,
that enamines 3b and 9 did not show any reactions with neat
pyrrolidine or in ethanol at reflux. Thus, the formation of 18b can be
considered as the initial step in the reaction cascade leading to the
salt 10b (Scheme 5).
After formation of 18, the unshared electron pair on nitrogen
kicks out fluoride to give the difluoroalkene derivative 22, which
easily gives the enamine 23 by nucleophilic addition of amine to the
activated double bond. One more fluoride extrusion/amine addition
continues the reaction leading to the monofluoro compound 25 via
24. The reaction is completed by the last fluoride extrusion to form
the final vinylogous guanidinium salts 10–17 or 21 (Scheme 5).
The reasons for the significant change in the position of nucle-
ophilic attack depending on the reaction conditions are not com-
pletely understood yet. Kinetic or thermodynamic control of the
reaction pathways is the most reasonable explanation. Since the
share of enamines 3b decreased by increasing reaction temperature
both in neat pyrrolidine and EtOH, one can conclude, that the en-
amines 3b are the kinetically favored primary products, while
compounds 18b (which in turn are transformed to 10) are favored
thermodynamically. This supposition is in a good agreement with
quantum chemical calculations [B3LYP/6-311þG(2d,2p)] of the heat
of formation of enamines 3b and 18b. E-18b is the thermodynam-
ically most stable compound, followed by Z-18b, Z-3b and E-3b
(2.14, 4.39 and 7.16 kcal/mol, respectively). However, the position
of the nucleophilic attack is also significantly determined by the
p-substituent in the aromatic ring. While only 3a was formed in the
reaction of the p-nitro compound 1a with pyrrolidine, the p-chloro
compound 2b gave a mixture of 3b and 18 (and its consecutive
products), and the p-methoxy derivative 2d gave only traces of 3d.
In the case of the reactions in solvents, also solvatation of the
amine must be taken into the account. As a consequence, the
b-halogen is not very important and both bromo- and chlorostyr-
enes gave the salts 10–17 in comparable yields (Table 2). Piperidine,
morpholine, dimethyl- and diethylamine also gave the expected
salts when reacted with 2b, while the reaction of this styrene with
piperazine led to a complex mixture of products. In all other cases
vinylogous guanidinium salts were found as the sole products and
only the styrene 2f with an ortho-bromine substituent gave a mix-
ture of the salt 12f and the enamine 4f by reaction with piperidine
in dioxane.
In order to clear up the possible reaction mechanism we fol-
lowed the progress of some reactions by 1H and 19F NMR spec-
troscopy. According to these experiments the reaction of
bromostyrene 2b with pyrrolidine in EtOH proceeded quite rapidly
even at room temperature and the starting material was com-
pletely consumed after less then 4 h. The reaction in EtOH as well as
in neat pyrrolidine afforded a mixture of five products. In addition
to Z-3b and E-3b, one of its regioisomers 18b, the corresponding
ketone 19b and the vinylogous guanidinium salt 10b were observed
in the reaction mixture by 1H and 19F NMR spectroscopy (Scheme 4,
Table 3).
CF3
Br
X
N
CF3
CF3
CF3
Ar
N
H
N
N
2b
N
O
CF3
N
Ar
N
CF3
Ar
Ar
Ar
Ar
E-3
19
Z-3
18
10 (X = Br)
21 (X = F)
Ar
20
Scheme 4. Reaction of styrene 2b and alkyne 20 with pyrrolidine.
Table 3
Time and temperature dependent product ratio of the reaction of styrene 2b and alkynes 20a, 20b and 20d with pyrrolidine
Compound
Ar
Solvent
T (ꢀC)
Time (h)
Z-3
E-3
18
19
10 or 21
2b
2b
2b
2b
2b
2b
2b
2b
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-NO2C6H4
4-ClC6H4
4-MeOC6H4
EtOH
EtOH
EtOH
EtOH
Neat
Neat
Neat
Neat
Neat
Neat
Neat
rt
rt
4
24
37
41
45
29
51
57
59
32
71
55
d
2
2
2
3
3
4
3
8
10
8
36
12
d
d
23
d
d
d
d
2
15
36
53
68
12
39
38
60
d
2
rt, then reflux
Reflux
rt
rt, then 80
rt, then 80
80
rt
rt
72, then 8
5
14
14, then 5
72, then 30
5
Overnight
Overnight
Overnight
d
d
11
d
d
d
d
35
87
20a
20b
20d
29
4
rt
d
9
4

V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 6991–7000
6995
F
F
F
F
F
CF3
CF3
+ HNR1R2
+ HNR1R2
-HF
1R2RN
1R2RN
H
H
X
1R2RN
F
X
-HX
Ar
Ar
Ar
Ar
18
22
1 or 2
F
NR2R1
F
NR2R1
F
F
NR2R1
+ HNR1R2
-HF
2R1RN
1R2RN
1R2RN
F
Ar
F
Ar
Ar
24
23
X
F
NR2R1
Ar NR2R1
10-17 or 21
1R2RN
NR2R1
2R1RN
-F
Ar NR2R1
25
Scheme 5. Possible pathway of formation of salts 10–17 and 21.
sterically more demanding solvated amine attacks the less hin-
dered -position of the styrene preferentially to give the
secondary amines strongly depends on the electronic properties of
the aromatic ring and the reactivity of the applied secondary amine.
Two different reaction pathways were observed. In case of very
reactive styrenes such as 1a, bearing the very strong electron-
withdrawing nitro group in the aromatic ring, the reactions always
proceeded as nucleophilic vinylic substitutions forming the corre-
sponding Z/E-isomeric enamines 3 with all used secondary amines.
Moreover, the most reactive secondary amine, pyrrolidine, gave the
enamines 3a from styrenes 1a both in a polar solvent and under
solvent free (neat) conditions. These reactions proceed via an ad-
dition–elimination mechanism. Less electron deficient styrenes
such as 2b, bearing a halogen atom in the aromatic ring, gave en-
amines only with neat secondary amines. With neat amines at el-
evated temperature or in solvents such as ethanol at reflux, the
reaction pathway changed significantly and a cascade of reactions
led to the vinylogous guanidinium salts 10–17 as the major reaction
products. Kinetic or thermodynamic control of the initial sub-
stitution step seems to be the reason for the different reaction
pathways.
a
regioisomers 18, which in turn are transformed to consecutive
products. However, more detailed experimental investigations of
the solvent effect and higher-level calculations of activation bar-
riers considering the solvent are necessary to get detailed in-
formation on the reaction pathway. Results of these ongoing
investigations will be published in due course.
Furthermore, there is the question of the mechanism of the
nucleophilic substitution of the vinylic halogen atoms. A number of
mechanisms were discussed in literature.21 Most frequently the
addition–elimination mechanism was postulated, starting with
a nucleophilic addition to the double bond to yield a carbanion,
followed by elimination of the leaving group. This pathway is fa-
cilitated by electron-withdrawing groups at the double bond and
by reactive anionic nucleophiles. Alternatively, strongly basic an-
ions can cause elimination of hydrogen halide followed by nucle-
ophilic addition towards a formed intermediate.
Earlier, an elimination–addition mechanism was suggested for
the reaction of b
-chlorostyrenes 1 with secondary lithium amides.16
It was shown that aryltrifluoromethylalkynes 20 reacted with
lithium amide of secondary amines to give Z-isomers of the en-
amine regio- and stereoselectively. We prepared the aryltri-
fluoromethylalkynes 20a, 20b, and 20d and examined their
reactions with pyrrolidine. In our hands these alkynes reacted
rapidly and smoothly with neat pyrrolidine at room temperature,
affording a mixture of products (Scheme 4, Table 3).
The reaction of the alkyne 20a with pyrrolidine led exclusively
to a mixture of Z- and E-isomers of 3a, while 1a (88:12 mixture of Z/
E-isomers) gave pure Z-3a under the same conditions. The less
electron deficient alkyne 20b afforded mainly Z-3b and minor
amounts of E-3b. The second major product was the enamine 18,
while only very small amounts of the vinylogous guanidinium salt
21 were formed. In the case of the electron rich alkyne 20c the
regioselectivity was completely opposite to the reaction of 20a
forming compound 18 almost exclusively. The enamines 3c were
not found and only 4% of 21 were detected.
4. Experimental
4.1. General
1H-, 13C- and 19F NMR spectra were recorded on Bruker ARX 300
and Bruker AMX 400 spectrometers in CDCl3, CD3CN with TMS,
CDCl3 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) and a Hewlett–
Packard HP 5971A instrument (EI, 70 eV). The alkynes 20,
and -bromo- -trifluoromethylstyrenes were synthesized
according to our previously reported procedures.5b,e,9
b-chloro-
1
b
b
2
4.2. Reactions of b-chloro- and b-bromo-b-
trifluoromethylstyrenes 1 and 2 with pyrrolidine
Summarizing these data, we can conclude that reactions of
-halostyrenes such as 1 and 2 with pyrrolidine do not occur via an
4.2.1. Reactions with neat secondary amines
b
A one neck 25 mL round bottomed flask was charged with dry
pyrrolidine (8.5 mL, 100 mmol), cooled down to ꢁ18 ꢀC and the
corresponding styrene (1 or 2, 10 mmol) was added in one portion
with vigorous stirring. The reaction mixture was stirred at room
temperature for 1–3 h until all starting styrene was consumed (TLC
monitoring). The excess of pyrrolidine was evaporated in vacuum,
the viscous residue was dissolved in CH2Cl2 (50 mL), washed with
water (3ꢂ50 mL) and dried over Na2SO4. CH2Cl2 was removed in
vacuo, and the residue was filtered through a short silica gel pad
using hexane or appropriate mixtures of hexane and CH2Cl2. The Z/
elimination–addition sequence in contrast to its reactions with
secondary lithium amides. The addition–elimination mechanism is
most probable for its reactions with secondary amines affording
enamines.
3. Conclusions
According to the experimental data, we can conclude that the
reaction pathway of
b-halo-b-trifluoromethylstyrenes with

6996
V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 6991–7000
E-isomers of enamines 3 could not be separated by column
chromatography.
4.2.1.6. 1-[2-(2-Nitrophenyl)-1-(trifluoromethyl)vinyl]pyrrolidine
(3h). Obtained as a 88:12 mixture of Z/E-isomers from styrene 1h
(2510 mg, 10 mmol). Yield 2802 mg (98%); yellow oil; IR (Nujol)
1340, 1530 (NO2), 1620 (C]C) cmꢁ1; Z-isomer: 1H NMR (400 MHz,
4.2.1.1. 1-[(1Z)-2-(4-Nitrophenyl)-1-(trifluoromethyl)vinyl]pyrroli-
dine (3a). Obtained from styrene 1a (2501 mg, 10 mmol). Yield
2717 mg (95%); yellow-orange crystals; mp 81–82 ꢀC; IR (Nujol)
CDCl3):
d 1.76–1.83 (m, 4H, 2NCH2CH2), 2.99–3.06 (m, 4H,
2NCH2CH2), 6.25 (s, 1H, CH]CCF3), 7.29–7.35 (m, 2H, Ar), 7.55 (td,
1330, 1510 (NO2), 1615 (C]C) cmꢁ1 1H NMR (400 MHz, CDCl3):
;
J¼8.6 Hz, J¼1.0 Hz, 1H, Ar), 7.96 (dd, J¼8.3 Hz, J¼1.0 Hz, 1H, Ar); 13C
d
1.86–1.91 (m, 4H, 2NCH2CH2), 3.08–3.14 (m, 4H, 2NCH2CH2), 6.06
NMR (100 MHz, CDCl3): d 25.5 (2NCH2CH2), 50.9 (2NCH2CH2), 100.1
(s, 1H, CH]CCF3), 7.29 (d, J¼8.7 Hz, 2H, Ar), 8.16 (d, J¼8.7 Hz, 2H,
(q, J¼6.6 Hz, CH]CCF3), 121.6 (q, J¼278.1 Hz, CF3), 135.8 (q,
Ar); 19F NMR (282 MHz, CDCl3):
CDCl3):
d
ꢁ64.7; 13C NMR (100 MHz,
J¼28.5 Hz, C–CF3), 124.3, 126.8, 131.8, 132.0, 137.0, 147.8 (Ar). E-
d
25.6 (2NCH2CH2), 51.2 (2NCH2CH2), 103.9 (q, J¼5.9 Hz,
isomer: 1H NMR (400 MHz, CDCl3):
d 1.95–2.01 (m, 4H, 2NCH2CH2),
3.17–3.31 (m, 4H, 2NCH2CH2), 5.78 (s, 1H, CH]CCF3), 7.51 (td,
CH]CCF3), 121.7 (q, J¼278.8 Hz, CF3), 136.6 (q, J¼29.3 Hz, C–CF3),
123.1, 129.2, 143.2, 145.3 (Ar); ESI-MS (m/z): calcd for
C13H13F3N2O2Na [Mþ] 309.0824, found 309.0821. Anal. Calcd for
C13H13F3N2O2: C 54.55; H 4.58. Found: C 54.81; H 4.61.
J¼7.6 Hz, J¼1.0 Hz, 1H, Ar); 13C NMR (100 MHz, CDCl3):
d 24.8
(2NCH2CH2), 49.3 (2NCH2CH2), 132.9 (q, J¼2.9 Hz, CH]CCF3), 124.1,
127.1, 133.8, 148.2 (Ar);the other signals are identical to those of
the Z-isomer. Anal. Calcd for C13H13F3N2O2: C 54.55; H 4.58.
Found: C 54.72; H 4.68.
4.2.1.2. 1-[(1Z)-2-(4-Chlorophenyl)-1-(trifluoromethyl)vinyl]pyrroli-
dine (3b). Obtained from styrene 2b (2860 mg, 10 mmol). Yield
1877 mg (68%); colorless oil; IR (Nujol) 1620 (C]C) cmꢁ1; 1H NMR
4.2.2. Reaction in THF with lithium amide of pyrrolidine
(400 MHz, CDCl3):
d
1.76–1.85 (m, 4H, 2NCH2CH2), 3.00–3.07 (m,
A previously heated one neck 25 mL round bottomed flask was
flushed with argon, charged with dry THF (50 mL), dry pyrrolidine
(1.67 mL, 20 mmol) and cooled down to ꢁ40 ꢀC. Next, 2.5 M solu-
tion of n-BuLi in hexane (8.8 mL, 22 mmol) was added dropwise
during 5 min. The reaction mixture was stirred another 30 min at
ꢁ30 to ꢁ40 ꢀC, cooled down to ꢁ78 ꢀC and the corresponding
styrenes (1) (10 mmol) were added dropwise at this temperature.
The reaction mixture was allowed to warm to room temperature
and quenched with saturated solution of NH4Cl. The organic phase
was separated and the water phase was extracted with ether
(3ꢂ20 mL). The combined extracts were washed with water
(2ꢂ50 mL) and dried over Na2SO4. The volatiles were removed in
vacuo, and the residue was filtered through a short silica gel pad
using hexane.
4H, 2NCH2CH2), 6.06 (s, 1H, CH]CCF3), 7.19 (d, J¼8.6 Hz, 2H, Ar),
7.25 (d, J¼8.6 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3):
d
ꢁ64.6; 13
C
NMR (100 MHz, CDCl3): d 25.5 (2NCH2CH2), 50.2 (2NCH2CH2), 108.2
(q, J¼5.9 Hz, CH]CCF3), 122.2 (q, J¼278.8 Hz, CF3), 134.1 (q,
J¼28.5 Hz, C–CF3), 127.9, 130.3, 131.8, 134.2 (Ar). Anal. Calcd for
C13H13ClF3N: C 56.63; H 4.75. Found: C 56.43; H 4.88.
4.2.1.3. Methyl 4-[(1Z)-3,3,3-trifluoro-2-pyrrolidin-1-ylprop-1-enil]-
benzoate (3e). Obtained from styrene 2e (3090 mg, 10 mmol). Yield
2542 mg (85%); colorless oil; IR (Nujol) 1610 (C]C), 1720 (C]O,
CO2Me) cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 1.82–1.89 (m, 4H,
2NCH2CH2), 3.04–3.11 (m, 4H, 2NCH2CH2), 3.93 (s, 3H, CO2CH3), 6.10
(s, 1H, CH]CCF3), 7.27 (d, J¼8.2 Hz, 2H, Ar), 7.98 (d, J¼8.2 Hz, 2H,
Ar); 13C NMR (100 MHz, CDCl3):
d 25.5 (2NCH2CH2), 50.6
(2NCH2CH2), 52.0 (CO2CH3), 106.4 (q, J¼5.9 Hz, CH]CCF3), 122.0 (q,
J¼278.8 Hz, CF3), 135.2 (q, J¼28.5 Hz, C–CF3), 127.4, 128.8, 129.0,
140.9 (Ar), 166.9 (CO2CH3). Anal. Calcd for C15H16F3NO2: C 60.20; H
5.39. Found: C 60.51; H 5.49.
4.2.2.1. 1-[(1Z)-2-Phenyl-1-(trifluoromethyl)vinyl]pyrrolidine (3c).
Obtained from styrene 1c (2070 mg, 10 mmol). Yield 1615 mg
(67%); colorless oil; IR (Nujol) 1610 (C]C) cmꢁ1
;
1H NMR
(400 MHz, CDCl3):
2NCH2CH2), 6.24 (s, 1H, CH]CCF3), 7.23–7.29 (m, 1H, Ar), 7.35–7.39
(m, 4H, Ar); 13C NMR (100 MHz, CDCl3):
25.5 (2NCH2CH2), 50.2
d 1.85–1.93 (m, 4H, 2NCH2CH2), 3.11–3.18 (m, 4H,
4.2.1.4. 1-[2-(2-Bromophenyl)-1-(trifluoromethyl)vinyl]pyrrolidine
(3f). Obtained as a 92:8 mixture of Z/E-isomers from styrene 2f
(3300 mg, 10 mmol). Yield 2400 mg (75%); colorless oil; IR (Nujol)
d
(2NCH2CH2), 110.0 (q, J¼5.9 Hz, CH]CCF3), 122.5 (q, J¼278.8 Hz,
CF3), 136.6 (q, J¼28.5 Hz, C–CF3), 126.5, 127.8, 129.3, 135.8 (Ar). 1H
NMR and 13C NMR spectra are in agreement with literature.10g
1610 (C]C) cmꢁ1; Z-isomer: 1H NMR (400 MHz, CDCl3):
d 1.79–1.86
(m, 4H, 2NCH2CH2), 3.04–3.11 (m, 4H, 2NCH2CH2), 6.07 (s, 1H,
CH]CCF3), 7.06 (td, J¼7.6 Hz, J¼1.5 Hz, 1H, Ar), 7.23–7.27 (m, 1H,
Ar), 7.29 (d, J¼7.6 Hz, 1H, Ar), 7.58 (dd, J¼7.8 Hz, J¼0.9 Hz, 1H, Ar);
4.2.2.2. 1-[(1Z)-2-(4-Methoxyphenyl)-1-(trifluoromethyl)vinyl]pyrro-
lidine (3d). Obtained from styrene 1d (2810 mg, 10 mmol). Yield
13C NMR (100 MHz, CDCl3):
d
25.6 (2NCH2CH2), 50.5 (2NCH2CH2),
1707 mg (63%); colorless oil; IR (Nujol) 1620 (C]C) cmꢁ1 1H
;
104.6 (q, J¼6.6 Hz, CH]CCF3), 122.2 (q, J¼278.2 Hz, CF3), 134.8 (q,
NMR (400 MHz, CDCl3): d 1.81–1.89 (m, 4H, 2NCH2CH2), 3.04–
J¼28.5 Hz, C–CF3), 124.5, 126.4, 127.6, 131.1, 132.1, 136.8 (Ar); E-
3.11 (m, 4H, 2NCH2CH2), 3.84 (s, 3H, OCH3), 6.21 (s, 1H,
CH]CCF3), 6.88 (d, J¼8.7 Hz, 2H, Ar), 7.34 (d, J¼8.7 Hz, 2H, Ar);
isomer: 1H NMR (400 MHz, CDCl3):
d 1.98–2.02 (m, 4H, 2NCH2CH2),
3.29–3.33 (m, 4H, 2NCH2CH2), 5.56 (s, 1H, CH]CCF3); 13C NMR
(100 MHz, CDCl3): 24.8 (2NCH2CH2), 49.3 (2NCH2CH2), 126.7,
13C NMR (100 MHz, CDCl3):
d 25.4 (2NCH2CH2), 49.9 (2NCH2CH2),
d
55.1 (OCH3), 112.9 (q, J¼5.1 Hz, CH]CCF3), 122.8 (q, J¼279.6 Hz,
CF3), 132.2 (q, J¼27.8 Hz, C–CF3), 113.4, 127.9, 130.6, 158.6 (Ar).
Anal. Calcd for C14H16F3NO: C 61.98; H 5.94. Found: C 61.85; H
5.88.
127.8, 137.4 (Ar); the other signals are identical to those of the Z-
isomer. Anal. Calcd for C13H13BrF3N: C 48.77; H 4.09. Found: C
48.47; H 4.30.
4.2.1.5. 1-[(1Z)-2-(3-Nitrophenyl)-1-(trifluoromethyl)vinyl]pyrro-
lidine (3g). Obtained from styrene 1g (2510 mg, 10 mmol). Yield
2231 mg (78%); yellow oil; IR (Nujol) 1330, 1510 (NO2), 1620 (C]C)
4.3. Reactions of styrene 1a with other secondary amines
The styrene 1a (500 mg, 2 mmol) and the corresponding
secondary amine (20 mmol) were heated in a sealed glass tube
with a Young-tap. The excess of secondary amine was evapo-
rated at reduced pressure and the residue was purified by col-
umn chromatography on silica gel (CH3OH/CH2Cl2 1:10 for
piperazine and pentane/CH2Cl2 2:1 for others). The Z- and E-
isomers of enamines 4–8 could not be separated by column
chromatography.
cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 1.84–1.91 (m, 4H, 2NCH2CH2),
3.05–3.12 (m, 4H, 2NCH2CH2), 6.09 (s, 1H, CH]CCF3), 7.44–7.54 (m,
2H, Ar), 8.01 (d, J¼8.1 Hz, 1H, Ar), 8.07 (br s, 1H, Ar); 13C NMR
(100 MHz, CDCl3):
d 25.5 (2NCH2CH2), 50.7 (2NCH2CH2), 105.0 (q,
J¼6.6 Hz, CH]CCF3), 121.9 (q, J¼278.8 Hz, CF3), 135.7 (q, J¼29.3 Hz,
C–CF3), 120.8, 123.2, 128.5, 134.7, 137.6, 147.9 (Ar). Anal. Calcd for
C13H13F3N2O2: C 54.55; H 4.58. Found: C 54.67; H 4.66.

V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 6991–7000
6997
4.3.1. 1-[2-(4-Nitrophenyl)-1-(trifluoromethyl)vinyl]piperidine(4a)
Obtained as a 83:17 mixture of Z/E-isomers by heating with
piperidine at 85 ꢀC for 2 h. Yield 534 mg (89%); yellow oil; Z-iso-
J¼280.8 Hz, CF3), 139.6 (q, J¼27.9 Hz, C–CF3), 123.5 (CH), 129.9 (CH),
141.1, 146.6 (Ar); E-isomer: 1H NMR (300 MHz, CDCl3):
d 6.08 (s, 1H,
CH]CCF3), 7.40 (d, J¼8.7 Hz, 2H, Ar), 8.15 (d, J¼8.7 Hz, 2H, Ar); 19
F
mer: 1H NMR (300 MHz, CDCl3):
d
1.51–1.67 (m, 6H), 2.86–2.98 (m,
NMR (282 MHz, CDCl3):
d
ꢁ58.0; 13C NMR (75 MHz, CDCl3):
d 50.5
4H, 2NCH2), 6.36 (s, 1H, CH]CCF3), 7.72 (d, J¼8.9 Hz, 2H, Ar), 8.21
(NCH2), 51.0 (OCH2), 114.0 (q, J¼2.0 Hz, CH]CCF3), 123.2 (CH), 129.7
(q, J¼2.0 Hz, CH), 142.3, 146.8 (Ar); the other signals are identical to
those of the Z-isomer. ESI-MS (m/z): calcd for C13H14F3N3O2H [Mþ]
302.1116, found 302.1111. Anal. Calcd for C13H14F3N3O2ꢂH2O: C
48.90; H 5.05; N 13.16. Found: C 49.12; H 4.68; N 13.35.
(d, J¼8.9 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3):
d
ꢁ63.4; 13C NMR
(75 MHz, CDCl3):
d 23.7 (NCH2CH2CH2), 26.1 (NCH2CH2CH2), 51.5
(NCH2), 115.2 (q, J¼5.5 Hz, CH]CCF3), 122.5 (q, J¼281.3 Hz, CF3),
140.6 (q, J¼27.9 Hz, C–CF3), 123.4 (CH), 129.7 (CH), 141.5, 146.5 (Ar);
E-isomer: 1H NMR (300 MHz, CDCl3):
d 1.67–1.76 (m, 6H), 6.05 (s,
1H, CH]CCF3), 7.39 (d, J¼8.8 Hz, 2H, Ar), 8.14 (d, J¼8.8 Hz, 2H, Ar);
4.3.5. N,N-Diethyl-N-[2-(4-nitrophenyl)-1-(trifluoromethyl)-
vinyl]amine (8)
19F NMR (282 MHz, CDCl3):
d
ꢁ58.1; 13C NMR (75 MHz, CDCl3):
d
23.8 (NCH2CH2CH2), 25.7 (NCH2CH2CH2), 51.7 (NCH2), 113.7 (q,
Obtained as a 88:12 mixture of Z/E-isomers by heating with
diethylamine at 85 ꢀC for 15 h. Yield 472 mg (82%); yellow-orange
J¼2.4 Hz, CH]CCF3), 142.4 (q, J¼30.1 Hz, C–CF3), 123.1 (CH), 129.6
(q, J¼2.4 Hz, CH), 142.6 (Ar); the other signals are identical to those
of the Z-isomer. ESI-MS (m/z): calcd for C14H15F3N2O2Na [Mþ]
323.0983, found 323.0978. Anal. Calcd for C14H15F3N2O2: C 56.00;
H 5.04; N 9.33. Found: C 55.48; H 4.96; N 9.53.
crystals; mp 34–37 ꢀC; Z-isomer: 1H NMR (300 MHz, CDCl3):
d 1.08
(t, J¼7.1 Hz, 6H, CH2CH3), 3.02 (t, J¼7.1 Hz, 4H, CH2CH3), 6.44 (s, 1H,
CH]CCF3), 7.67 (d, J¼8.8 Hz, 2H, Ar), 8.20 (d, J¼8.8 Hz, 2H, Ar); 19
F
NMR (282 MHz, CDCl3):
d
ꢁ63.7; 13C NMR (75 MHz, CDCl3):
d 13.5
(CH3), 46.2 (CH2), 116.2 (q, J¼5.1 Hz, CH]CCF3), 122.5 (q,
J¼281.6 Hz, CF3), 138.2 (q, J¼28.5 Hz, C–CF3), 123.6 (CH), 129.5 (CH),
4.3.2. 1-[2-(4-Nitrophenyl)-1-(trifluoromethyl)vinyl]azepane (5)
Obtained as a 96:4 mixture of Z/E-isomers by heating with
hexamethylenamin at 125 ꢀC for 8 h. Yield 490 mg (78%); yellow-
orange crystals; mp 64–67 ꢀC; Z-isomer: 1H NMR (300 MHz,
141.8, 146.5 (Ar); E-isomer: 1H NMR (300 MHz, CDCl3):
d 1.16 (t,
J¼7.0 Hz, 6H, CH2CH3), 3.14 (t, J¼7.0 Hz, 4H, CH2CH3), 5.98 (s, 1H,
CH]CCF3), 7.39 (d, J¼8.7 Hz, 2H, Ar), 8.15 (d, J¼8.7 Hz, 2H, Ar); 19
F
CDCl3):
d
1.57–1.72 (m, 8H), 3.01–3.13 (m, 4H, 2NCH2), 6.33 (s, 1H,
NMR (282 MHz, CDCl3):
d
ꢁ58.6; 13C NMR (75 MHz, CDCl3):
d 11.6
CH]CCF3), 7.48 (d, J¼8.8 Hz, 2H, Ar), 8.20 (d, J¼8.8 Hz, 2H, Ar); 19
F
(CH3), 45.3 (CH2),114.5 (q, J¼2.6 Hz, CH]CCF3),123.2 (CH),129.6 (d,
J¼2.6 Hz, CH), 143.1, 146.4 (Ar); the other signals are identical to
those of the Z-isomer. ESI-MS (m/z): calcd for C13H15F3N2O2Na [Mþ]
311.0983, found 311.0980. Anal. Calcd for C13H15F3N2O2: C 54.17; H
5.24; N 9.72. Found: C 54.29; H 5.33; N 9.57.
NMR (282 MHz, CDCl3):
d
ꢁ64.4; 13C NMR (75 MHz, CDCl3):
d 28.2
(NCH2CH2CH2), 29.1 (NCH2CH2CH2), 53.6 (NCH2), 113.6 (q, J¼5.0 Hz,
CH]CCF3), 122.5 (q, J¼280.5 Hz, CF3), 141.1 (q, J¼29.0 Hz, C–CF3),
123.6 (CH), 129.4 (CH), 142.2, 146.3 (Ar); E-isomer: 1H NMR
(300 MHz, CDCl3):
d 1.74–1.84 (m, 6H), 3.25–3.33 (m, 4H, 2NCH2),
5.80 (s, 1H, CH]CCF3), 7.32 (d, J¼8.8 Hz, 2H, Ar), 8.11 (d, J¼8.8 Hz,
4.3.6. 3,3,3-Trifluoro-1-(2-nitrophenyl)-N,N-dipropyl-1-propen-2-
amine (9)
2H, Ar); 19F NMR (282 MHz, CDCl3):
CDCl3):
d
ꢁ56.9; 13C NMR (75 MHz,
d
28.1 (NCH2CH2CH2), 28.8 (NCH2CH2CH2), 53.5 (NCH2),
A one neck 25 mL round bottomed flask was charged with N,N-
dipropylamine (1010 mg, 10 mmol), EtOH (2.5 mL) and the styrene
1h (377 mg, 1.5 mmol). The reaction mixture was stirred at reflux
for 5 h until all starting materials were consumed (TLC monitor-
ing). The volatiles were evaporated in vacuum and the residue
was purified by column chromatography on silica gel using
(hexane/ether, 1:3) to yield the enamine 9 as a mixture (88:12) of
Z/E-isomers. Yield 334 mg (53%); yellow-orange oil; IR (film) 1623
143.0 (q, J¼31.6 Hz, C–CF3), 123.1 (CH), 129.8 (q, J¼2.6 Hz, CH),
144.2, 145.9 (Ar); the other signals are identical to those of the Z-
isomer. ESI-MS (m/z): calcd for C15H17F3N2O2Na [Mþ] 337.1140,
found 337.1134. Anal. Calcd for C15H17F3N2O2: C 57.32; H 5.45; N
8.91. Found: C 57.64; H 5.47; N 8.91.
4.3.3. 1-[2-(4-Nitrophenyl)-1-(trifluoromethyl)vinyl]morpholine (6)
Obtained as a 71:29 mixture of Z/E-isomers by heating with
morpholine at 125 ꢀC for 8 h. Yield 509 mg (84%); yellow crystals;
(C]C) cmꢁ1; Z-isomer: 1H NMR (400 MHz, CDCl3):
d 0.74 (t,
J¼7.4 Hz, 6H), 1.30–1.50 (m, 4H), 2.72 (t, J¼7.4 Hz, 4H), 6.57 (s, 1H),
mp 87–90 ꢀC; Z-isomer: 1H NMR (300 MHz, CDCl3):
d
2.95–3.04 (m,
7.35–7.40 (m, 1H), 7.42–7.50 (m, 1H), 7.52–7.60 (m, 1H), 7.95–7.85
4H, NCH2CH2O), 3.71–3.78 (m, 4H, NCH2CH2O), 6.50 (s, 1H,
(m, 1H); 19F NMR (377 MHz, CDCl3):
d
ꢁ63.9; 13C NMR (100 MHz,
CH]CCF3), 7.80 (d, J¼8.9 Hz, 2H, Ar), 8.23 (d, J¼8.9 Hz, 2H, Ar); 19
F
50.4
CDCl3):
d
11.5 (CH3), 21.5 (CH2), 54.4 (NCH2), 112.4 (q, J¼5.4 Hz,
NMR (282 MHz, CDCl3):
d
ꢁ63.5; 13C NMR (75 MHz, CDCl3):
d
]CH), 122.7 (q, J¼280.3 Hz, CF3), 124.8 (C-3), 128.2 (C-4), 131.5 (C-
1), 131.6 (C-6), 132.7 (C-5), 140.0 (q, J¼28.4 Hz, C–N), 147.0 (C-2);
(NCH2), 66.8 (OCH2), 117.4 (q, J¼5.5 Hz, CH]CCF3), 122.2 (q,
J¼280.8 Hz, CF3), 139.2 (q, J¼28.1 Hz, C–CF3), 123.6 (CH), 129.9 (CH),
E-isomer: 1H NMR (400 MHz, CDCl3):
d
0.91 (t, J¼7.4 Hz, 6H), 1.55–
140.7, 146.9 (Ar); E-isomer: 1H NMR (300 MHz, CDCl3):
d
3.81–3.86
1.65 (m, 4H), 2.97 (t, J¼7.4 Hz, 4H), 6.26 (s, 1H), 7.35–7.40 (m, 1H),
(m, 4H, NCH2CH2O), 6.10 (s, 1H, CH]CCF3), 7.40 (d, J¼8.8 Hz, 2H,
7.42–7.50 (m, 1H), 7.52–7.60 (m, 1H), 7.95–7.85 (m, 1H); 19F NMR
Ar), 8.17 (d, J¼8.8 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3):
d
ꢁ58.0;
(377 MHz, CDCl3):
d
ꢁ58.3; 13C NMR (100 MHz, CDCl3):
d 11.7
13C NMR (75 MHz, CDCl3):
d
50.8 (NCH2), 66.5 (OCH2), 114.5 (q,
(CH3), 20.0 (CH2), 53.9 (NCH2), 112.4 (q, J¼5.4 Hz, ]CH), 122.7 (q,
J¼280.3 Hz, CF3), 124.6 (C-3), 128.2 (C-4), 131.5 (C-1), 131.6 (C-6),
132.4 (C-5), 140.0 (q, J¼28.4 Hz, C–N), 147.0 (C-2); mass spectrum
(m/z, %): 316 (14), 287 (57), 198 (53), 43 (100). Anal. Calcd for
C15H19F3N2O2: C 56.96; H 6.05; N 8.86. Found: C 56.86; H 6.22, N
9.01.
J¼2.4 Hz, CH]CCF3), 141.4 (q, J¼30.5 Hz, C–CF3), 123.2 (CH), 129.6
(q, J¼2.4 Hz, CH), 141.9, 146.7 (Ar); the other signals are identical to
those of the Z-isomer. ESI-MS (m/z): calcd for C13H13F3N2O3Na [Mþ]
325.0776, found 325.0771. Anal. Calcd for C13H13F3N2O3: C 51.66; H
4.34; N 9.27. Found: C 51.84; H 4.12; N 9.41.
4.3.4. 1-[2-(4-Nitrophenyl)-1-(trifluoromethyl)vinyl]piperazine (7)
Obtained as a 95:5 mixture of Z/E-isomers by heating with pi-
perazine at 125 ꢀC for 8 h. Yield 550 mg (92%); yellow-orange
crystals; mp 72–76 ꢀC; Z-isomer: 1H NMR (300 MHz, CDCl3):
4.4. 1-[(1Z)-2-(2-Bromophenyl)-1-(trifluoromethyl)-
vinyl]piperidine (4f)
The styrene 2f (330 mg, 1 mmol) and piperidine (850 mg,
10 mmol) were refluxed in dioxane (2 mL) for 10 h. The volatiles
were evaporated in vacuum and the residue was purified by column
chromatography on silica gel. Gradient elution by ether/hexane 1:1
and CHCl3/CH3OH 9:1 mixtures afforded enamine 4f (173 mg, 52%)
d
2.51–2.63 (br s, 3H), 2.91–3.11 (br s, 3H), 6.43 (s, 1H, CH]CCF3),
7.76 (d, J¼8.8 Hz, 2H, Ar), 8.21 (d, J¼8.8 Hz, 2H, Ar); 19F NMR
(282 MHz, CDCl3):
d
ꢁ63.5; 13C NMR (75 MHz, CDCl3):
d 50.3
(NCH2), 51.4 (NCH2), 116.0 (q, J¼5.5 Hz, CH]CCF3), 122.3 (q,

6998
V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 6991–7000
and salt 12f (182 mg, 35%). Spectroscopic data of compound 12f see
below.
4.5.3. 1-[(2E)-3-(4-Chlorophenyl)-1,3-dipyrrolidin-1-ylprop-2-
enylidene]pyrrolidinium chloride (11b)
Obtained as a 70:30 mixture of Z/E-isomers. Yellow-orange
Obtained from styrene 1b (482 mg, 2 mmol) and pyrrolidine by
heating in THF (5 mL) at 85–88 ꢀC for 17 h. Yield 583 mg (74%);
oil; IR (Nujol) 1636 (C]C) cmꢁ1; Z-isomer: 1H NMR (400 MHz,
CDCl3):
d
1.40–1.75 (m, 6H), 2.75–2.85 (m, 4H, 2NCH2), 6.46 (s,
white crystals, mp 110–112 ꢀC; 1H NMR (300 MHz, CDCl3):
d 1.61–
1H, CH]CCF3), 7.05–7.15 (m, 1H), 7.25–7.35 (m, 1H), 7.50–7.60 (m,
1.80 (br s, 8H), 1.91–2.07 (br s, 4H), 3.23–3.42 (br s, 4H), 3.42–3.55
2H); 19F NMR (377 MHz, CDCl3):
CDCl3):
d
ꢁ63.8; 13C NMR (100 MHz,
(br s, 8H), 4.79 (s, 1H, Ar–C]CH), 7.39 (d, J¼8.4 Hz, 2H, Ar), 7.51 (d,
d
24.1 (NCH2CH2CH2), 26.3 (NCH2CH2CH2), 51.7 (NCH2),
J¼8.4 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3):
d 24.9 (NCH2CH2), 25.2
116.4 (q, J¼5.1 Hz, CH]CCF3), 123.0 (q, J¼280.0 Hz, CF3), 139.3 (q,
(NCH2CH2), 50.3 (NCH2CH2), 85.4 (Ar–C]CH), 158.0 (Ar–C]CH),
162.8 (N–C]N), 129.0 (CH), 130.0 (CH), 133.6, 136.4 (Ar); ESI-MS
(m/z) calcd for C21H29ClNþ3 [Mþ]: 358.2045, found 358.2045. Anal.
Calcd for C21H29ClN3ꢂH2O: C 61.16; H 7.58; N 10.19. Found: C 61.08;
H 7.53; N 10.09.
J¼28.4 Hz, C–CF3), 124.5, 126.9 (CH), 129.0 (CH), 131.1 (CH), 132.6
(CH), 135.7 (Ar); E-isomer: 1H NMR (400 MHz, CDCl3):
d 2.90–
3.00 (m, 4H, 2NCH2), 6.00 (s, 1H, CH]CCF3); 19F NMR (377 MHz,
CDCl3):
d
ꢁ58.4; 13C NMR (100 MHz, CDCl3):
d
26.0
(NCH2CH2CH2), 51.9 (NCH2), 116.7 (q, J¼2.1 Hz, CH]CCF3), 122.3
(q, J¼278.0 Hz, CF3), 142.3 (q, J¼29.6 Hz, C–CF3), 125.0, 127.0 (CH),
128.8 (CH), 130.9 (CH), 132.1 (CH), 136.2 (Ar); the other signals
are identical to those of the Z-isomer. Mass spectrum (m/z, %):
335 (Mþþ1, 63), 333 (Mþ–1, 63), 254 (100), 178 (84). Anal. Calcd
for C14H15BrF3N: C 50.32; H 4.52; N 4.19. Found: C 50.06; H 4.35;
N 4.21.
4.5.4. 1-[(2E)-3-(4-Methoxyphenyl)-1,3-dipyrrolidin-1-ylprop-2-
enylidene]pyrrolidinium chloride (11d)
Obtained from styrene 1d (474 mg, 2 mmol) and neat pyrroli-
dine by heating at 85–88 ꢀC for 16 h. Yield 679 mg (87%); pale
brown crystals, mp 98–99 ꢀC; 1H NMR (300 MHz, CDCl3):
d 1.62–
1.77 (br s, 8H), 1.85–2.16 (br s, 4H), 3.20–3.36 (br s, 4H), 3.36–3.48
(br s, 8H), 3.87 (s, 3H, MeO), 4.57 (s,1H, Ar–C]CH), 7.01 (d, J¼8.8 Hz,
2H, Ar), 7.25 (d, J¼8.8 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3):
d 25.0
4.5. Synthesis of vinylogous guanidinium salts 10–17
(NCH2CH2), 25.3 (NCH2CH2), 51.5 (NCH2CH2), 55.6 (MeO), 84.8 (Ar–
C]CH), 159.6 (Ar–C]CH), 161.3 (N–C]N), 114.1 (CH), 127.3, 130.0
(CH),163.4 (Ar); ESI-MS (m/z) calcd for C22H32N3Oþ [Mþ]: 354.2540,
found 354.2540. Anal. Calcd for C22H32ClN3OꢂH2O: C 64.77; H 8.40;
N 10.30. Found: C 64.36; H 8.32; N 10.09.
The corresponding styrene 1, 2 (0.5–2 mmol), the secondary
amine (5–20 mmol) and the solventy (1.5–5 mL of EtOH, THF or di-
oxane)wereheatedinasealedglasstubewithaYoung-tap. Theexcess
of secondary amine was evaporated at reduced pressure and the
residue was purified by column chromatography on silica gel (CHCl3/
CH3OH 9:1).
4.5.5. 1-[(2E)-3-(4-Bromophenyl)-1,3-dipyrrolidin-1-ylprop-2-
enylidene]pyrrolidinium chloride (11i)
Obtained from styrene 1i (285 mg, 1 mmol) and pyrrolidine
(355 mg, 5 mmol) by reflux in EtOH (5 mL) for 6 h. Yield 57 mg
4.5.1. 1-[(2E)-3-(4-Chlorophenyl)-1,3-dipyrrolidin-1-ylprop-2-
enylidene]pyrrolidinium bromide (10b)
(13%); 1H NMR (400 MHz, CDCl3):
d 1.55–1.75 (br s, 8H), 1.85–2.05
Obtained from styrene 2b (143 mg, 0.5 mmol) and pyrrolidine
(365 mg, 5 mmol) by reflux in EtOH (1.5 mL) for 6 h. Yield
283 mg (86%); colorless crystals, mp 41 ꢀC; IR (Nujol) 1549,
(br s, 4H), 3.15–3.35 (br s, 4H), 3.35–3.50 (br s, 8H), 4.66 (s, 1H), 7.24
(d, J¼8.2 Hz, 2H), 7.61 (d, J¼8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
1573 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 1.55–1.70 (br s, 8H),
d
25.2, 25.5 (CH2), 52.0 (NCH2), 86.1 (]CH), 124.9 (C-4), 130.5 (C-
3,5), 132.3 (C-2,6), 134.4 (C-1), 158.2 (]C–N), 163.2 (N–C–N). Anal.
Calcd for C21H29BrClN3: C 57.48; H 6.66; N 9.58. Found: C 57.09; H
7.01; N 9.28.
1.80–2.05 (br s, 4H), 3.10–3.30 (br s, 4H), 3.30–3.50 (br s, 8H),
4.61 (s, 1H), 7.30 (d, J¼8.5 Hz, 2H), 7.43 (d, J¼8.5 Hz, 2H); 13C
NMR (100 MHz, CDCl3):
d 25.1, 25.4 (CH2), 51.4, 52.0 (NCH2), 86.1
(]CH), 129.2 (C-3,5), 130.4 (C-2,6), 133.8 (C-1), 136.6 (C-4), 158.1
(]C–N), 163.0 (N–C–N); 1H NMR (400 MHz, CD3CN):
d
1.55–1.65
4.5.6. 1-[(2E)-3-Pyridin-2-yl-1,3-dipyrrolidin-1-ylprop-2-
enylidene]pyrrolidinium chloride (11j)
(br s, 8H), 1.85–2.05 (br s, 4H), 3.15–3.30 (br s, 4H), 3.30–3.45 (br
Obtained from styrene 1j (416 mg, 2 mmol) and pyrrolidine by
heating in THF (5 mL) at 85–88 ꢀC for 16 h. Yield 533 mg (74%);
green-gray crystals, mp 117–119 ꢀC; 1H NMR (300 MHz, CDCl3):
s, 8H), 4.60 (s, 1H), 7.37 (d, J¼8.5 Hz, 2H), 7.49 (d, J¼8.5 Hz, 2H);
13C NMR (100 MHz, CD3CN):
d 26.1, 26.5 (CH2), 51.3, 52.7 (NCH2),
86.7 (]CH), 130.0 (C-3,5), 132.1 (C-2,6), 135.9 (C-1), 137.0 (C-4),
159.5 (]C–N), 164.5 (N–C–N); mass spectrum (m/z, %): 286
(100), 185 (72), 169 (50), 75 (39). Anal. Calcd for C21H29BrClN3: C
57.48; H 6.66; Br 18.21; Cl 8.08; N 9.58. Found: C 57.54; H 6.58;
Br 17.89; Cl 7.85; N 9.35.
d
1.62–1.74 (br s, 8H), 1.96–2.04 (br s, 4H), 3.27–3.38 (br s, 4H),
3.43–3.53 (br s, 8H), 4.70 (s, 1H, –C]CH), 7.46 (ddd, J¼7.8 Hz,
J¼4.8 Hz, J¼0.9 Hz, 1H, Py), 7.71 (d, J¼7.8 Hz, 1H, Py), 8.14 (td,
J¼7.8 Hz, J¼1.8 Hz, 1H, Py), 8.66 (ddd, J¼4.8 Hz, J¼1.8 Hz, J¼0.9 Hz,
1H, Py); 13C NMR (75 MHz, CDCl3):
d 24.9 (NCH2CH2), 25.0
(NCH2CH2), 49.8 (NCH2CH2), 51.5 (NCH2CH2), 85.4 (Ar–C]CH),
156.8 (Ar–C]CH), 162.7 (N–C]N), 124.8 (CH), 124.9 (CH), 137.6
(CH), 149.2 (CH), 153.4 (Ar); ESI-MS (m/z) calcd for C20H29Nþ4 [Mþ]:
325.2387, found 325.2387.
4.5.2. 1-[(2E)-3-(4-Methoxyphenyl)-1,3-dipyrrolidin-1-ylprop-2-
enylidene]pyrrolidinium bromide (10d)
Obtained from styrene 2d (211 mg, 0.75 mmol) and pyrrolidine
(550 mg, 7.5 mmol) by reflux in EtOH (2 mL) for 6 h. Yꢁie1ld 167 mg
;
1H NMR
(76%); colorless crystals, mp 213 ꢀC; IR (KBr) 1534 cm
4.5.7. 1-[(2E)-3-(4-Chlorophenyl)-1,3-dipiperidin-1-ylprop-2-
enylidene]piperidinium bromide (12b)
(400 MHz, CDCl3): d 1.35–1.60 (br s, 8H), 1.65–1.90 (br s, 4H), 3.00–
3.15 (br s, 4H), 3.15–3.35 (br s, 8H), 3.61 (s, 3H), 4.43 (s, 1H), 6.77 (d,
J¼8.2 Hz, 2H), 7.06 (d, J¼8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
Obtained from styrene 2b (572 mg, 2 mmol) and piperidine by
heating in EtOH (5 mL) at 120 ꢀC for 16 h. Yield 632 mg (66%);
d
24.4, 24.7 (CH2), 50.9 (NCH2), 54.8 (CH3O), 84.9 (]CH), 113.5 (C-
yellow powder, mp 123–125 ꢀC; 1H NMR (300 MHz, CDCl3):
d 1.46–
3,5), 126.7 (C-1), 129.6 (C-2,6), 158.4 (]C–N), 160.5 (N–C–N), 162.6
(C-4). Anal. Calcd for C22H32BrN3O: C 60.83; H 7.42; N 9.67. Found: C
60.47; H 7.22, N 9.49.
1.84 (m, 18H), 2.99–3.65 (br s, 12H), 4.89 (s, 1H, Ar–C]CH), 7.33 (d,
J¼8.5 Hz, 2H, Ar), 7.57 (d, J¼8.5 Hz, 2H, Ar); 13C NMR (75 MHz,
CDCl3):
d 23.5, 23.7, 25.5, 25.7, 50.9 (NCH2), 52.1 (NCH2), 88.4 (Ar–
C]CH), 165.1 (Ar–C]CH), 169.0 (N–C]N), 129.6 (CH), 130.7 (CH),
133.1, 137.1 (Ar); ESI-MS (m/z) calcd for C24H35ClNþ3 [Mþ]: 400.2514,
found 400.2514.
y
In the case of salts 11d, 14, 15, and 17 the reactions were carried out without
solvent.

V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 6991–7000
6999
4.5.8. 1-[(2E)-3-(4-Methoxyphenyl)-1,3-dipiperidin-1-ylprop-2-
enylidene]piperidinium bromide (12d)
4H), 4.76 (s, 1H, Ar–C]CH), 7.00 (d, J¼8.6 Hz, 2H, Ar), 7.18 (d,
J¼8.6 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3):
d 47.4 (NCH2CH2O),
Obtained from styrene 2b (562 mg, 2 mmol) and piperidine by
heating in EtOH (5 mL) at 120 ꢀC for 16 h. Yield 400 mg (42%);
51.1 (NCH2CH2O), 66.0 (NCH2CH2O), 66.5 (NCH2CH2O), 88.0 (Ar–
C]CH), 167.7 (Ar–C]CH), 170.3 (N–C]N), 114.6 (CH), 122.8 (CH),
131.0, 153.3 (Ar); ESI-MS (m/z) calcd for C25H37N4Oþ4 [Mþ]:
457.2809, found 457.2809. Anal. Calcd for C25H37BrN4O4: C 55.86; H
6.94; N 10.42. Found: C 55.70; H 7.19; N 9.56.
yellow-brown viscous oil; 1H NMR (300 MHz, CDCl3):
d 1.43–1.84
(m, 18H), 3.10–3.66 (br s, 12H), 3.89 (s, 3H, MeO), 4.72 (s, 1H, Ar–
C]CH), 7.08 (d, J¼9.0 Hz, 2H, Ar), 7.25 (d, J¼9.0 Hz, 2H, Ar); 13C
NMR (75 MHz, CDCl3):
d 23.5, 23.8, 25.5, 25.8, 51.0 (NCH2), 51.8
(NCH2), 55.7 (MeO), 87.0 (Ar–C]CH), 166.8 (Ar–C]CH), 169.7 (N–
C]N), 114.7 (CH), 126.4 (CH), 130.8, 161.7 (Ar); ESI-MS (m/z) calcd
for C25H38N3Oþ [Mþ]: 396.3009, found 396.3009.
4.5.14. N-[(2E)-3-(4-Chlorophenyl)-1,3-bis(diethylamino)prop-2-
enylidene]-N,N-diethylammonium bromide (17)
Obtained from styrene 2b (572 mg, 2 mmol) and diethylamine by
heating in neat at 130 ꢀC for 75 h. Yield 590 mg (66%); pale brown
4.5.9. 1-[(2E)-3-(2-Bromophenyl)-1,3-dipiperidin-1-ylprop-2-
enylidene]piperidinium bromide (12f)
Obtained from styrene 2f (330 mg, 1 mmol) and piperidine
(850 mg, 10 mmol) as a mixture with 1-[2-(2-bromophenyl)-1-(tri-
fluoromethyl)vinyl]piperidine (4f) by reflux in dioxane (2 mL) for
10 h. Yield 182 mg (35%); viscous oil; IR (KBr) 1535 cmꢁ1; 1H NMR
crystals, mp 135–136 ꢀC; 1H NMR (300 MHz, CDCl3):
d 0.79–1.18 (m,
15H, CH3),1.27–1.52 (brs, 3H, CH3), 2.97–3.18(brs, 2H, CH2), 3.18–3.42
(br s, 8H, CH2), 3.54–3.74(brs,2H, CH2), 4.77(s,1H, Ar–C]CH), 7.34(d,
J¼8.4 Hz, 2H, Ar), 7.55 (d, J¼8.4 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3):
d
11.5 (CH3), 12.4 (CH3), 13.9 (CH3), 44.8 (CH2), 45.3 (CH2), 45.6 (CH2),
86.2 (Ar–C]CH),163.8 (Ar–C]CH),169.8 (N–C]N),129.2 (CH),129.5
(CH), 133.1, 136.3 (Ar); ESI-MS (m/z) calcd for C21H35ClNþ3 [Mþ]:
364.2514, found 364.2514. Anal. Calcd for C21H35BrClN3ꢂCHCl3: C
46.79; H 6.51; N 7.44. Found: C 47.10; H 6.45; N 7.38.
(400 MHz, CDCl3):
d
1.30–1.80 (br s, 18H), 2.70–3.70 (br s, 12H), 4.79
23.4, 23.6,
(s, 1H), 7.15–7.65 (m, 4H); 13C NMR (100 MHz, CDCl3):
d
25.3 (CH2), 52.0 (NCH2), 88.2 (]CH), 122.0 (C-2), 128.6 (C-4), 131.8
(C-6), 131.9 (C-5), 133.9 (C-3), 134.3 (C-1), 162.5 (]C–N), 167.9 (N–
C–N). Anal. Calcd for C24H35Br2N3,: C 54.87; H 6.72; N 8.00. Found: C
54.74; H 6.59; N 8.25.
4.6. Reactions of acetylenes 20 with pyrrolidine
The corresponding acetylene 20 (0.5 mmol) and pyrrolidine
(0.43 mL, 5 mmol) were mixed and allowed to stay for 2 h at room
temperature. The volatiles were evaporated in vacuum and the
residue was investigated by NMR spectroscopy.
4.5.10. 1-[(2E)-3-(4-Methylphenyl)-1,3-dipiperidin-1-ylprop-2-
enylidene]piperidinium bromide (12k)
Obtained from styrene 2k (265 mg, 1 mmol) and piperidine by
heating in EtOH (2 mL) at 110 ꢀC for 9 h. Yield 180 mg (39%); col-
orless crystals, mp 118–119 ꢀC; IR (KBr) 1512, 1534 cmꢁ1
;
1H NMR
4.6.1. 1-[(1E)-2-(4-Nitrophenyl)-1-(trifluoromethyl)vinyl]-
pyrrolidine (3a)
(400 MHz, CDCl3):
12H), 4.28 (s,1H), 6.65 (br s, 2H), 6.90 (br s, 2H); 13C NMR (100 MHz,
CDCl3): 21.1 (CH3), 23.3, 23.5, 25.3, 25.5 (CH2), 50.7, 51.7 (NCH2),
d 1.10–1.40 (br s,18H),1.98 (s, 3H), 2.65–3.20 (br s,
Obtained from acetylene 20a as a mixture with Z-isomer. 1H
d
NMR (300 MHz, CDCl3): d 1.95–2.00 (m, 4H, 2NCH2CH2), 3.28–3.32
87.3 (]CH),128.8 (C-3,5),129.6 (C-2,6),131.5 (C-1),141.4 (C-4),165.6
(]C–N),169.4 (N–C–N). Anal. Calcd for C25H38BrN3: C 65.21; H 8.32;
Br 17.35; N 9.12. Found: C 64.93; H 8.70; Br 17.02; N 8.80.
(m, 4H, 2NCH2CH2), 5.48 (s, 1H, CH]CCF3), 7.28 (d, J¼8.6 Hz, 2H,
Ar), 8.11 (d, J¼8.6 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3):
ꢁ58.59;
d
13C NMR (75 MHz, CDCl3):
d 25.0 (2NCH2CH2), 49.5 (2NCH2CH2),
102.5 (q, J¼3.2 Hz, CH]CCF3), 144.0 (q, J¼32.9 Hz, C–CF3), 129.6 (q,
J¼2.6 Hz, CH), 144.4 (Ar); the other signals are identical to those of
the Z-isomer.
4.5.11. 1-[(2E)-3-(4-Bromophenyl)-1,3-dipiperidin-1-ylprop-2-
enylidene]piperidinium chloride (13)
Obtained from styrene 1j (285 mg, 1 mmol) and piperidine by
heating in EtOH (2 mL) at 110 ꢀC for 13 h. Yield 283 mg (59%);
4.6.2. 1-[1-(4-Methoxyphenyl)-2-(trifluoromethyl)vinyl]-
pyrrolidine (18d)
colorless crystals, mp 135 ꢀC; IR (KBr) 1536 cmꢁ1
;
1H NMR
(400 MHz, CDCl3):
d
1.20–1.65 (br s, 18H), 2.80–3.50 (br s, 12H), 4.55
Obtained from acetylene 20c as a mixture with 3,3,3-trifluoro-
1-(4-methoxyphenyl)propan-1-one (19d) and 1-[(2E)-3-(4-meth-
oxyphenyl)-1,3-dipyrrolidin-1-ylprop-2-enylidene]pyrrolidinium
(s, 1H), 6.95–7.05 (br s, 2H), 7.49 (d, J¼7.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3):
d 23.3, 23.5, 25.3, 25.5 (CH2), 50.7, 51.8 (NCH2),
88.1 (]CH), 125.2 (C-4), 130.6 (C-3,5), 132.3 (C-2,6), 133.4 (C-1),
165.0 (]C–N), 168.8 (N–C–N). Anal. Calcd for C24H35BrClN3: C
59.94; H 7.34; N 8.74. Found: C 59.81; H 7.12; N 8.78.
fluoride (21d). 18d: 1H NMR (300 MHz, CDCl3):
d 1.80–1.94 (m, 4H,
2NCH2CH2), 2.94–3.07 (m, 4H, 2NCH2CH2), 3.81 (s, 3H, OCH3), 4.27
(q, J¼7.9 Hz, 1H, C]CHCF3), 6.90 (d, J¼8.7 Hz, 2H, Ar), 7.20 (d,
J¼8.7 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3):
ꢁ48.0 (d, J¼7.9 Hz);
d
4.5.12. 1-[(2E)-1,3-Diazepan-1-yl-3-(4-chlorophenyl)prop-2-
enylidene]azepanium bromide (14)
13C NMR (75 MHz, CDCl3):
d 25.4 (2NCH2CH2), 48.4 (2NCH2CH2),
55.2 (OCH3), 83.4 (q, J¼35.2 Hz, C]CHCF3), 126.6 (q, J¼265.3 Hz,
Obtained from styrene 2b (572 mg, 2 mmol) and hexamethyle-
nediamine by heating in neat at 130 ꢀC for 75 h. Yield 785 mg (75%);
CF3), 154.6 (q, J¼4.7 Hz, C]CHCF3), 113.4 (CH), 129.7 (CH), 128.3,
159.6 (Ar); 19d: 1H NMR (300 MHz, CDCl3):
d
3.74 (q, J¼10.2 Hz, 2H,
viscous yellow oil; 1H NMR (300 MHz, CDCl3):
d
1.39–1.82 (br s,
CH2CF3), 3.88 (s, 3H, OCH3), 6.96 (d, J¼9.0 Hz, 2H, Ar), 7.92 (d,
24H), 3.13–3.55 (br s, 12H), 4.82 (s, 1H, Ar–C]CH), 7.39 (d, J¼8.6 Hz,
J¼9.0 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3):
ꢁ62.0 (t, J¼10.2 Hz).
d
2H, Ar), 7.56 (d, J¼8.6 Hz, 2H, Ar); 13C NMR (75 MHz, CDCl3):
d
26.7,
1H NMR and 13C NMR spectra of compound 19d are in agreement
26.9, 27.2, 28.3 (CH2), 53.0, 54.1 (NCH2), 86.4 (Ar–C]CH), 164.1 (Ar–
C]CH),170.6 (N–C]N),129.4 (CH),130.6 (CH),133.0,136.9 (Ar); ESI-
MS (m/z) calcd for C27H41N3Clþ [Mþ]: 442.2984, found 442.2984.
with literature.22
4.6.3. 1-[(1E)-2-(4-Chlorophenyl)-1-(trifluoromethyl)vinyl]-
pyrrolidine (3b)
4.5.13. 4-[(2E)-1,3-Dimorpholin-4-yl-3-(4-morpholin-4-ylphenyl)-
prop-2-enylidene]morpholin-4-ium bromide (15)
Obtained from acetylene 20b as a mixture with Z-isomer,
1-[1-(4-chlorophenyl)-2-(trifluoromethyl)vinyl]pyrrolidine (18b),
3,3,3-trifluoro-1-(4-chlorophenyl)propan-1-one 19b and 1-[(2E)-
3-(4-chlorophenyl)-1,3-dipyrrolidin-1-ylprop-2-enylidene]pyrroli-
Obtained from styrene 2b (572 mg, 2 mmol) and morpholine by
heating in neat at 130 ꢀC for 75 h. Yield 344 mg (32%); yellowish
crystals, mp 223–225 ꢀC; 1H NMR (300 MHz, CDCl3):
d
3.13–3.51
dinium fluoride (21b). 3b: 1H NMR (300 MHz, CDCl3):
d
1.90–1.98
(m, 16H), 3.61–3.73 (br s, 8H), 3.74–3.84 (br s, 4H), 3.86 (t, J¼4.8 Hz,
(m, 4H, 2NCH2CH2), 3.15–3.22 (m, 4H, 2NCH2CH2), 5.55 (s, 1H,

7000
V.M. Muzalevskiy et al. / Tetrahedron 65 (2009) 6991–7000
CH]CCF3); 19F NMR (282 MHz, CDCl3):
d
ꢁ58.5; 18b: 1H NMR
3. (a) Hudlicky´, M.; Pavlath, A. P. Chemistry of Organic Fluorine Compounds II. ACS
Symposium Series 187; American Chemical Society: Washington, DC, 1995;
Enantiocontrolled Synthesis of Fluoro-Organic Compounds; Soloshonok, V. A., Ed.;
Wiley & Sons: Chichester, UK, 1999; (b) Asymmetric Fluoroorganic Chemistry.
Synthesis, Applications, and Future Directions; Ramachandran, P. V., Ed.; ACS
Symposium Series 746; American Chemical Society: Washington, DC, 2000; (c)
Fluorine-Containing Synthons; Soloshonok, V. A., Ed.; ACS Symposium Series 911;
American Chemical Society: Washington, DC, 2005; (d) Scienceof Synthesis; Percy,
J. M., Ed.; Fluorine; Thieme: Stuttgart, 2006; Vol. 34; (e) Current Fluoroorganic
Chemistry. New Synthetic Directions, Technologies, Materials, and Biological Appli-
cations; Soloshonok, V. A., Mikami, K., Yamazaki, T., Welch, J. T., Honek, J. F., Eds.;
ACS Symposium Series 949; American Chemical Society: Washington, DC, 2006.
4. (a) Shastin, A. V.; Korotchenko, V. N.; Nenajdenko, V. G.; Balenkova, E. S. Tet-
rahedron 2000, 56, 6557–6563; (b) Korotchenko, V. N.; Shastin, A. V.; Ne-
najdenko, V. G.; Balenkova, E. S. Synthesis 2001, 2081–2084; (c) Korotchenko, V.
N.; Shastin, A. V.; Nenajdenko, V. G.; Balenkova, E. S. J. Chem. Soc., Perkin Trans. 1
2002, 883–887; (d) Shastin, A. V.; Nenajdenko, V. G.; Korotchenko, V. N.; Ba-
lenkova, E. S. Russ. Chem. Bull. 2001, 50, 1401–1405; (e) Korotchenko, V. N.;
Nenajdenko, V. G.; Shastin, A. V.; Balenkova, E. S. Org. Biomol. Chem. 2003,
1906–1908; (f) Nenajdenko, V. G.; Korotchenko, V. N.; Shastin, A. V.; Balenkova,
E. S. Russ. Chem. Bull. 2004, 53, 1034–1064.
5. (a) Nenajdenko, V. G.; Shastin, A. V.; Korotchenko, V. N.; Varseev, G. N.; Ba-
lenkova, E. S. Eur. J. Org. Chem. 2003, 302–308; (b) Korotchenko, V. N.; Shastin,
A. V.; Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron 2001, 57, 7519–7527; (c)
Nenajdenko, V. G.; Varseev, G. N.; Korotchenko, V. N.; Shastin, A. V.; Balenkova,
E. S. J. Fluorine Chem. 2003, 124, 115–118; (d) Nenajdenko, V. G.; Varseev, G. N.;
Korotchenko, V. N.; Shastin, A. V.; Balenkova, E. S. J. Fluorine Chem. 2004, 125,
1339–1345; (e) Nenajdenko, V. G.; Varseev, G. N.; Shastin, A. V.; Balenkova, E. S.
J. Fluorine Chem. 2005, 126, 907–913; (f) Shastin, A. V.; Muzalevsky, V. M.; Ba-
lenkova, E. S.; Nenajdenko, V. G. Mendeleev Commun. 2006, 16, 179–180.
6. Nenajdenko, V. G.; Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Haufe, G.
J. Fluorine Chem. 2007, 128, 818–826.
(300 MHz, CDCl3):
d 1.84–1.90 (m, 4H, 2NCH2CH2), 2.93–3.02 (m,
4H, 2NCH2CH2), 4.30 (q, J¼7.9 Hz, 1H, C]CHCF3), 7.21 (d, J¼8.5 Hz,
2H, Ar), 7.36 (d, J¼8.5 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3):
d
ꢁ48.2 (d, J¼7.9 Hz); 13C NMR (75 MHz, CDCl3):
d 25.3 (2NCH2CH2),
48.5 (2NCH2CH2), 84.0 (q, J¼35.4 Hz, C]CHCF3), 128.4 (CH), 129.8
(q, J¼1.3 Hz, CH), 133.9 (Ar); 19b: 1H NMR (300 MHz, CDCl3):
d 3.77
(q, J¼9.9 Hz, 2H, CH2CF3), 7.49 (d, J¼8.7 Hz, 2H, Ar), 7.89 (d,
J¼8.7 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3):
ꢁ62.0 (t, J¼9.9 Hz).
d
NMR spectra of compound 19b are in agreement with literature.23
4.7. X-ray structure analysis
The single crystal diffraction data for compound 10b were
collected on a SMART APEX CCD (Bruker AXS) automatic diffracto-
meter (Mo K
a
,
l
¼0.71073 Å). The structure was solved by direct
methods and refined by the full-matrix least-squares method in an
anisotropic approximation for non-hydrogen atoms. The positions
of the H atoms were mostly calculated. The methyl H atoms were
refined with isotropic thermal parameters. Structure solution and
refinement calculations were carried out with SHELX-97 and
Bruker SHELXTL Version 6.12 program packages.
10b$H2O: C21H31BrClN3O; FW¼456.85; T¼240 K; Monoclinic,
P21/c; a¼12.8773(19); b¼8.7456(13); c¼19.939(3) Å;
b
¼93.492(2)ꢀ;
V¼2241.3(6) Å3;
Z¼4,
DC¼1.354 g/cm3;
m
¼1.969 mmꢁ1
;
7. Shastin, A. V.; Muzalevskiy, V. M.; Balenkova, E. S.; Nenajdenko, V. G.; Fro¨hlich,
R.; Haufe, G. Tetrahedron 2008, 64, 9725–9732.
8. Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Nenajdenko, V. G. Russ.
Chem. Bull. 2007, 56, 1526–1533.
9. Muzalevskiy, V. M.; Nenajdenko, V. G.; Shastin, A. V.; Balenkova, E. S.; Haufe, G.
Synthesis 2009, 2249–2259.
10. (a) Uneyama, K.; Morimoto, O.; Yamashita, F. Tetrahedron Lett. 1989, 30, 4821–
4824; (b) Gerus, I. I.; Gorbunova, M. G.; Kukhar, V. P. J. Fluorine Chem. 1994,
69, 195–198; (c) Cen, W.; Ni, Y.; Shen, V. J. Fluorine Chem. 1995, 73, 161–164;
(d) Bu¨rger, H.; Dittmar, T.; Pawelke, G. J. Fluorine Chem. 1995, 70, 89–93; (e)
Kurykia, M. A.; Volpin, I. M.; German, L. S. J. Fluorine Chem. 1996, 80, 9–12; (f)
Sanin, A. V.; Nenajdenko, V. G.; Smolko, K. I.; Denisenko, D. I.; Balenkova, E. S.
2.51<
q
<23.35ꢀ; 16,736 collected, 3259 unique, Rint¼0.1217; 369
parameters; Goof¼0.946;
R
indices for I>2
s
R1¼0.0448,
wR2¼0.1084; R indices (all data) R1¼0.0551, wR2¼0.1120.
Crystallographic data (excluding structure factors) for the
structure of 10b$H2O have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication CCDC-
725313. Copies of the data can be obtained, free of charge, on ap-
plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
þ44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk.
´
´
Synthesis 1998, 842–846; (g) Begue, J. P.; Bonnet-Delpon, D.; Bouvet, D.; Rock,
M. H. J. Chem. Soc., Perkin Trans. 1 1998, 1797–1800; (h) Moon Park, H.; Uegaki,
T.; Konno, T.; Ishihara, T.; Yamanaka, H. Tetrahedron Lett. 1999, 40, 2985–2988.
Acknowledgements
´
´
´
11. Begue, J. P.; Bonnet-Delpon, D.; Mesureur, D.; Nee, G.; Wu, S. W. J. Org. Chem.
1992, 57, 3807–3814.
´
´
12. Begue, J. P.; Mesureur, D. Synthesis 1989, 309–312.
This
project
was
supported
by
the
Deutsche
13. (a) Soloshonok, V. A.; Ono, T. Synlett 1996, 919–921; (b) Bravo, P.; Crucianelli,
M.; Zanda, M. Tetrahedron Lett. 1995, 36, 3043–3046.
14. Rulev, A. Yu. Usp. Khim. 2002, 71, 225–254; Russ. Chem. Rev. 2002, 71, 195–221.
15. Dmowski, W. J. Fluorine Chem. 1984, 26, 379–394.
Forschungsgemeinschaft (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 and 08-03-00067-a). The
authors are grateful to Oliver Mimkes and Jakub Grajewski, Mu¨nster,
for preliminary quantum chemical calculations.
16. Jiang, B.; Zhang, F. J.; Xiong, W. N. Tetrahedron 2002, 58, 261–264.
17. Hansen, P. E. Prog. Nucl. Magn. Reson. Spectrosc. 1981, 14, 175–296.
18. (a) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Chem. Rev. 1994, 94, 373–431;
(b) Burdeniuc, J.; Jedlicka, B.; Crabtree, R. H. Chem. Ber./Recueil 1997,130,145–154;
(c) Richmond, T. G. Angew. Chem., Int. Ed. 2000, 39, 3241–3244; (d) Richmond, T. G.
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1996, 118, 2525–2526; (g) Hughes, R. P.; Smith, J. M. J. Am. Chem. Soc. 1999, 121,
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1061–1071; (i) Kraft, B. M.; Lachicotte, R. J.; Jones, W. D. J. Am. Chem. Soc. 2000,122,
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