Mechanistic study of multi-step nucleophilic substitution for trifluoromethylated styrenes

Article abstract of DOI:10.1016/j.jfluchem.2011.07.015

The key steps of the reactions of nitrogen nucleophiles with β-halogen-β-trifluoromethylstyrenes have been studied by ¹⁹F and ¹H NMR monitoring and quantum-chemical calculations. In contrast to the mechanism proposed earlier for nucl

Full text of DOI:10.1016/j.jfluchem.2011.07.015

Journal of Fluorine Chemistry 132 (2011) 945–950
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Mechanistic study of multi-step nucleophilic substitution for trifluoromethylated
styrenes
Alexander Yu. Rulev a, , Igor A. Ushakov a,1, Evgeniy V. Kondrashov a,1, Vasiliy M. Muzalevskiy b,2
,
*
b,**
Aleksey V. Shastin c, Valentine G. Nenajdenko
a A.E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1, Favorsky Str., Irkutsk 664033, Russia
b Moscow State University, Department of Chemistry, Leninskie Gory, Moscow 119992, Russia
c Institute of Problems of Chemical Physics, Chernogolovka, Moscow Region 142432, Russia
A R T I C L E I N F O
A B S T R A C T
Article history:
The key steps of the reactions of nitrogen nucleophiles with
b
-halogen-
b
-trifluoromethylstyrenes have
been studied by 19F and 1H NMR monitoring and quantum-chemical calculations. In contrast to the
mechanism proposed earlier for nucleophilic vinylic substitution of captodative carbonyl-bearing
haloalkenes, this reaction proceeds via either E–Ad or Ad–E sequence depending on the nature of
aromatic substituents of the parent styrenes.
Received 16 June 2011
Received in revised form 16 July 2011
Accepted 18 July 2011
Available online 23 July 2011
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Reaction mechanisms
b-Halo-
b-trifluoromethylstyrenes
Amines
Domino reactions
1. Introduction
nucleophiles. In spite of the transformation looks simple by now,
many mechanistic variants of SNVin processes have been proposed
Nucleophilic vinylic substitution (SNVin) is a general type of
reactions for the synthesis of variety of unsaturated heteroatomic
systems including biologically important compounds [1]. It is well
known that the substitution of inactivated vinyl halides is a very
difficult process. But it is facilitated if an electron-withdrawing
depending on the structure of initial substrate or nucleophile,
nature of the leaving group, experimental conditions [1]. The most
versatile among b-activated (push–pull olefins) includes two-step
addition–elimination sequence. However, some vinylic systems
can undergo a much more complicated substitution. Thus, the
formation of captodative carbonyl-bearing aminoalkenes is a multi
step (Ad-SN2-E) process and occurs via nucleophilic addition of one
equivalent of amine to the activated double bond of the initial
substrate, followed by classical substitution of the halogen atom at
the sp3-carbon center by second amine equivalent and finally an
group is present in the
b-(push–pull olefins) or a-position
(captodative olefins) to the leaving group. It should be noted,
however, that for both cases the reaction does not occur as a direct
nucleophilic substitution of the halogen atom at the double bond.
Thus, among the different approaches to the captodative
aminoalkenes, the nucleophilic vinylic substitution of the halide
ion by the nitrogen nucleophile seems to be the more attractive
method for its simplicity [2]. Previously this methodology was
successfully applied to the synthesis of captodative enamines
bearing carbonyl, formyl, alkoxycarbonyl or cyano functionalities
[2,3].
elimination of
b-amine to produce captodative enamine derivative
(Scheme 1) [2a].
Our interest in the chemistry of captodative systems, in
particular aminoalkenes, led us to research of the new type of
captodative enamines bearing perfluoroalkyl group as an acceptor
[4]. The fluorine-bearing enamines are the target compounds for
chemical, medicinal and agricultural research. At the beginning of
21st century the interest for both captodative and push–pull
trifluoromethylated enamines has grown due to their remarkable
and specific properties as well as to their application as potential
precursors of various fluorine-containing biologically active
acyclic and heterocyclic compounds [5]. In contrast to early
studied aminoalkenes, these derivatives have an electron-with-
The result of SNVin reaction is the replacement of an
appropriate leaving group (for example, halogen) by various
* Corresponding author. Fax: +7 395 2419346.
** Corresponding author. Fax: +7 495 9328846.
E-mail addresses: rulev@irioch.irk.ru (A.Yu. Rulev), nen@acylium.chem.msu.ru
(V.G. Nenajdenko).
1
drawing group which is not capable to
p,p-conjugation with the
Fax: +7 395 2419346.
2
double bond. Recently, we have found that the unusual reactions of
Fax: +7 495 9328846.
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.07.015

946
A.Y. Rulev et al. / Journal of Fluorine Chemistry 132 (2011) 945–950
EWG
EWG
NuH
CF3
NR1
for 2b,c
for 2d-f
Ar
Ar
R
R
NuH
X
Nu
CF3
CF3
HNu
Ar
Ar
3a-d
X
1a,b
Nu
2a-f
CF3
R2N
4a-c
NR3
Nu
Nu
NuH
NuH
EWG
EWG
R
R
Scheme 3. The reactions of N-nucleophiles with EWG-substituted styrenes. 1–4:
Ar = 4-O2NC6H4; 1: X = Cl (a), X = F (b); 2: Nu = N(CH2)4 (a), NHCy (b), NHPri (c),
NH(CH2)2NH2 (d), NH(CH2)2NHMe (e), NMe(CH2)2NHMe (f); 3: NR1 = NCy (a),
NHPri (b), N(CH2)2NH2 (c), N(CH2)2NHMe (d); and 4: R2 = R3 = H (a), R2 = H, R3 = Me
(b), R2 = R3 = Me (c).
X
Nu
HX
Scheme 1. The general scheme of formation of captodative carbonyl-bearing
aminoalkenes. EWG = CHO, C(O)R, COOR, CN.
trifluoromethylated bromo- and chlorostyrenes with nitrogen
nucleophiles are synthetically valuable and mechanistically
intriguing processes leading to either target enamines or surpris-
ing products of CF3 group cleavage [6–8]. We have shown that the
direction of transformations depends dramatically on the nature of
aromatic substituent of initial substrate: styrenes bearing an
electron-withdrawing group are converted into trifluoromethy-
lated enamines (secondary amines) and/or azomethines (primary
amines) or heterocycles (binucleophiles) while their analogs
bearing electron-donor group in benzene ring give unexpected
products of nucleophilic C–F bond cleavage (primary or secondary
amines) or fragmentation (binucleophiles) (Scheme 2).
There still remains a question: what are the key steps of the
intricate processes and how the nature of the aromatic substituent
influences the reaction mechanism and direction of the transfor-
mation? A clear understanding of the mechanism of these
transformations is essential for their confident realization. In
previous papers [6–8] we have proposed a hypothetical scheme of
the synthesis of the major reaction products. Our recent
experimental and theoretical research has been devoted to its
clarification and corroboration. Here, we report the results of the
comprehensive study of the mechanism of these non-trivial
transformations.
approximately a minute after mixing (see Supporting Information,
Section 1.1). These signals were assigned by NOESY experiments to
the Z- and E-isomers of the enamine 2a. Both the geometric
isomers of 1a reacted simultaneously and the target product 2a
was formed as a (75:25) mixture of Z- and E-isomers. An important
observation was made upon the monitoring: the Z/E isomer ratio of
the product remained constant during the course of the reaction.
The kinetic of the reaction obtained by 19F NMR reveals
simultaneous disappearance of E- and Z-isomers of 1a and
formation of 2a as the mixture of E- and Z-isomers (Fig. 1). Any
other signals were not observed during all time of the monitoring.
Similar to secondary amines, isopropyl- or cyclohexylamine react
with styrene 1a very easily at room temperature. But in these cases
the enamines 2b,c are formed along with their tautomers 3a,b (see
Supporting Information, Section 1.2).
A similar experiment was performed with styrene 1b bearing
fluorine as a leaving group. When styrene 1b was treated with
pyrrolidine in methanol, only signals of enamine 2a as a reaction
product together with the singlet of anion Fꢀ (ca. ꢀ143 ppm) were
observed. Starting from 10:1 mixture of Z/E-1b the substitution of
the fluorine atom afforded the enamine 2a as an equimolar
mixture of geometric isomers. The 19F NMR monitoring in MeOH at
room temperature has clearly indicated that the reaction results in
the formation of target product 2a only which was isolated by
column chromatography in 96% yield.
2. Results and discussion
Next we have monitored the reaction of styrenes 1a,b with
ethylenediamine and its N-methyl- or N,N0-dimethylsubstituted
derivatives. When styrene 1b was treated with ethylenediamine,
the spectrum taken after 30 min shows singlets of 1b along with
low intensity resonances of enamine E,Z-2d (ꢀ63.1 and
ꢀ69.2 ppm) and its azomethine tautomer E,Z-3c (ꢀ72.4 and
ꢀ74.1 ppm). The intensities of these signals were increased for the
initial 2 h and after that they were decreased gradually during all
time of the monitoring. Simultaneously, the intensity of the singlet
of the heterocycle 4a (ꢀ80.5 ppm) was increased and its content
reached 85% of the reaction mixture after 16 h. Because the
2.1. Styrenes bearing electron-withdrawing substituent
In a first set of experiments we have monitored by 19F and 1H
NMR spectroscopy the reactions of amines with styrenes bearing
an electron-withdrawing substituent in the benzene ring (Scheme
3). The treatment of styrene 1a with a six molar excess of
pyrrolidine in methanol at room temperature results in the rapid
disappearance of the initial substrate 19F signals (ꢀ69.8 (Z-isomer)
and ꢀ62.4 ppm (E-isomer)) and subsequent appearance of two
new resonances (ꢀ65.5 and ꢀ59.3 ppm) which are observed
HNR1R2 RHN
CF3
NR1
for R2 = H
CF3
CF3
Z
ZH
Ar
Ar
Ar
NR1R2
RN
Y = EWG
CF3
Y
X
1
Y = EDG
RHN
NH2
Ar
R1R2N
Ar
NR1R2
X
RN
N
HNR1R2
NR1R2
Scheme 2. The reactivity of trifluoromethylated styrenes.

A.Y. Rulev et al. / Journal of Fluorine Chemistry 132 (2011) 945–950
947
Reaction product 2a
Initial styrene 1a
80
70
60
50
40
30
20
10
0
80
70
60
50
40
30
20
10
0
E- 1a
Z-1a
E-2a
Z-2a
0
50
100
150
200
0
50
100
150
200
min
min
Fig. 1. The integrated peak intensity in 19F NMR spectra as a function of time for the reaction of styrene 1a with pyrrolidine.
intensities of the signals of the intermediates 2d and 3c were low
during the course of the reaction we can conclude that both the
enamine or azomethine formation and their cyclization occurs
simultaneously with approximately equal reaction rate. Similar
results were observed for the reaction of 1a,b with N-methyl- and
N,N0-dimethylethylenediamine (see Supporting Information,
Section 1.3).
It should be noted that the reaction of 1b with N,N0-
dimethylethylenediamine proceeds more slowly. Moreover, after
1.5 h the 19F NMR spectra of the reaction mixture with N-
methylethylenediamine indicated the formation of two pairs of
intermediates – azomethines 3d and enamines 2e (Z/E-isomers
mixtures). This means that the reaction proceeds highly chemo-
selectively and the primary amino group reacts more easily with
alkenes 1. Probably this selectivity can be explained by sterical
control of the reaction with bulky CF3 group.
The results obtained can be explained in terms of multi-step
process, which includes the initial formation of the ipso-substitu-
tion products 2a–f. Taking into account a rich array of the possible
mechanisms of nucleophilic vinylic substitution [1b] we should
suggest that aminostyrenes 2a–f are formed via addition–
elimination (Ad–E) sequence. Although in all these cases any
intermediate of the transformations of halostyrenes 1a,b into
substitution products 2a–f was not observed and the general
mechanism is still a matter of debate, there are significant
arguments for the corroboration of the Ad–E pathway.
Strong confirmation of Ad–E mechanism for the 1a is obtained
by comparison of the vicinal coupling constants between CF3
carbon atom and olefinic proton (3JH,CF = 5.5 Hz for both com-
pounds 1a and 2a). Their value let us to conclude that the major
isomer of enamine 2a and initial styrene 1a have the same
geometry. As a rule Ad–E mechanism gave the retention of the
configuration of the double bond of alkene [1c]. The first step of the
sequence is the perpendicular attack of amine on the double bond
to form carbanion Y. After 608 turn the conformation for anti-
elimination is formed. Finally it gives the alkene with retention of
configuration (Scheme 4).
should be much higher for fluorine-bearing styrene 1b because the
strongly electron-withdrawing fluorine increases the electrophi-
licity of the attacked carbon atom. To study the effect of leaving
group the equimolar mixture of styrenes 1a and 1b in methanol
was treated with 15-fold excess of pyrrolidine at room tempera-
ture and next was monitored by 19F NMR spectroscopy. The
reaction of 1b went to completion in 5 h and the target enamine 2a
was formed as a (1:1) mixture of Z/E-isomers. In contrast, even
after an extended reaction time up to 10 h the large amount (20%)
of styrene 1a was remained. No other signals were detected during
the course of the reaction. Therefore, the styrene 1b has
demonstrated much higher activity in comparison with its analog
1a in the SNVin reaction confirming again Ad–E mechanism.
It should be noted that the stereochemical result of the reaction
of 1b is not so strict compared to 1a. However, the formation 1/1
diastereomers mixture in the case of fluorine as a nucleophuge can
be again rationalized in the frames of Ad–E mechanism. Fluorine is
a bad leaving group, from the other hand it stabilizes significantly
the carbanion Y. As a result Y (X = F) has longer life time and can be
protonated and further dehydrohalogenated to give final mixture
of Z/E isomers 2a in 1/1 ratio.
The preference only of the
a-addition of amines to the double
bond of the starting styrenes 1a,b can be easily explained by means
of the electronic effects. 4-Nitrophenyl and trifluoromethyl groups
have similar values of inductive constants (
s
I) and electronegativ-
= 2.98 for 4-NO2C6H4; I = 0.32–0.41
x = 2.32 for CF3 [9]. At the same time 4-nitrophenyl group
ity (
and
x
) (
sI = 0.26–0.34 and
x
s
possess very strong negative mesomeric effect, which should lead
to the appearance of some positive charge at the C olefinic carbon
a
atom. As a result, the nucleophilic attack is regioselective and
occurs at the
a-position of the double bond to the electron-
withdrawing function [10]. Such polarization of the double bond
can be also confirmed by referring to the 13C NMR data. Thus, it is
well known that the difference in the chemical shifts of two
adjacent carbon atoms can be used for estimation of the degree of
double bond polarization [11]. According to 13C NMR spectra, the
differences
d
(C ) ꢀ
d(C ) reach 17 ppm for 1a,b. Therefore, the
b
a
It could be predicted that if the reaction of styrenes 1a,b with
nitrogen nucleophiles proceeds according to Ad–E scheme, its rate
nucleophilic attack on the C olefinic carbon atom of starting
a
materials 1a,b is preferable and styrene 1b should be more active
Nu
Nu
Ar
Ar
H
CF3
Nu
Ar
H
CF3
Nu
Ar
H
CF3
X
CF3
-X
H
X
X
Y
Scheme 4. Mechanism of the reaction of EWG-substituted styrenes with N-nucleophiles.

948
A.Y. Rulev et al. / Journal of Fluorine Chemistry 132 (2011) 945–950
Intermediates of reaction
Initial styrene 1c
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
E-6a
5
E-1c
Z-1c
0
50
100
150
200
250
0
50
100
150
200
250
min
min
Fig. 2. The integrated peak intensity in 19F NMR spectra as a function of time for the reaction of styrene 1c with pyrrolidine.
in the nucleophilic addition reaction. Moreover, the substitution
proceeds via carbanion in which the negative charge is effectively
stabilized by the aryl group bearing an electron-withdrawing
substituent. Since the last step of the sequence (halide ion
elimination) is much faster than the amine addition, the proposed
intermediate could not be detected by 19F NMR.
We also performed quantum-chemical calculations at the MP2/
6-311 + G(d,p) level to clarify the mechanism for the regioselec-
tivity of the nucleophilic attack on the double bond of the styrenes
1a,b. The styrenes bearing electron-withdrawing (NO2) aromatic
substituent and either fluorine or chlorine at the olefinic carbon
atom were chosen as a model compounds in the reaction with
methylamine. In the case of styrene 1a bearing chlorine as a
After some minutes of mixing the doublet at ꢀ48.4 ppm
(3J(F,H) = 7.9 Hz) was appeared in 19F NMR spectra. NMR data (1D
(1H, 13C, 19F)) of this intermediate are in good agreement to those
previously reported for the enamine 6a, which was the product of
amine addition to acetylene 5 [6]. 2D NMR (HMBC, NOESY)
experiments confirmed additionally the structure of enamine 6a.
The simultaneous increasing of its intensity and decreasing of
intensity of 5 was observed during further progress of the reaction
(Fig. 2). The intermediate 6a undergoes further transformations as
we described previously to form salts 8a [6].
Therefore, alkenes bearing EDG react in alternative pathway via
an elimination–addition sequence. This conclusion was made after
the study of the reaction of styrene 1c with both primary and
secondary amines as well as diamines (see Supporting Information,
Sections 2.1 and 2.2). Scheme 5 shows the stepwise reaction
between styrene 1c and nitrogen nucleophiles, including the
proposed principal intermediates 5–7. The results obtained
suggest a stepwise mechanism (E–Ad) including the formation
of acetylenic derivative 5 as a key intermediate.
leaving group the formation of
a-adduct is preferred over the b-
one by 5.9 kcal/mol, whereas for the fluorinated analog 1b this
value is 9.2 kcal/mol.
2.2. Styrenes bearing electron-donor substituent
Next we tested the behavior of styrene 1c bearing an
electron-donor substituent in the aromatic ring. Accordingly
NMR data the treatment of 1c with 10–15-fold excess of
pyrrolidine results in its rapid dehydrobromination and forma-
tion of acetylene 5 [12]. It is important to note that in contrast to
styrenes 1a,b, Z- and E-isomers of 1c have different activity.
According to the 19F NMR spectra the E-1c does not react at all
with pyrrolidine while styrene Z-1c disappeared completely for
3 h at room temperature (Fig. 2, Scheme 5). This result can be
explained in terms of preferable anti-elimination of HBr to form
acetylene 5 only from Z-1c.
Finally, all principal intermediates were also registered in the
reaction of styrene 1c with binucleophiles. For detecting inter-
mediates, the reactions were monitored with excess of ethylene-
diamine or its N-methyl- or N,N0-dimethyl substituted derivatives
at room temperature without any solvent. Under these conditions,
acetylene 5 was formed almost exclusively for the first 5 min of
reaction of styrene 1c with ethylenediamine. In some minutes, the
intensity of the signal at ꢀ48.9 ppm (acetylene 5) has begun to
decrease and three new low-intensity signals (ca. 5–15%) have
appeared. Judging by their multiplicity and chemical shift values, a
doublet at ꢀ46.6 ppm (3J (F,H) = 7.6 Hz) was assigned to enamine
6d and two triplets at ꢀ60.7 and ꢀ62.2 (3J (F,H) = 10.7 Hz) were
attributed to its azomethine isomer 7c (Scheme 6). Then, a new
triplet at ꢀ60.1 ppm (3J (F,H) = 11.4 Hz) has appeared which was
attributed to imidazolidine 9a. Notice that the reaction of
binucleophiles with styrene 1c occurred as anti-addition process
leading to the formation of only one of two possible geometric
isomers of the enamine 6d: no other signal of this derivative has
been detected in 19F NMR spectra. After 1 h of the reaction the
singlet of acetylene 5 was disappeared completely, the intensities
of all multiplets have begun to decrease and finally the signal of
fluoride anion has appeared due to the fragmentation of the
products of substitution of all fluorine atoms of CF3 group.
In principle, it is possible to imagine more complex situation
when the electronic influence of the substituents in benzene ring
for styrenes 1 is intermediate between 4-nitro and 4-methoxy
groups. In this case both mechanisms of substitution could
be observed. In fact, the reaction of 4-chloro substituted styrene
1d with ethylenediamine really gave both types of the products [8].
HNu
HNR1R2
CF3
Ar
Ar
CF3
5
Br
NuH
HBr
1c
NR1R2
secondary
amine
Br
CF3
R1R2N
Ar
NR1R2
NR1R2
Ar
6a
NR1
8a-c
6b,c
primary
amines
CF3
Ar
7a,b
Scheme 5. The reactions of amines with EDG-substituted styrenes. 6,8:
NR1R2 = N(CH2)4 (a), NHPri (b), NHCy (c); 7: R1 = Pri (a), Cy (b).

A.Y. Rulev et al. / Journal of Fluorine Chemistry 132 (2011) 945–950
949
H
N
H
N
H
N
R2
R2
R1
N
R1
N
N
H
R1
CF3
6d-f
CF3
7c,d
Ar
Ar
R2
Ar
N
N R1
CF3
Ar
CF3
5
9a-c
HBr
R2
R1
N
CF3
R1
N
Ar
H
N
Br
1c
Ar
N
N
R1
10a,b
N
H
Scheme 6. The reactions of binucleophiles with EDG-substituted styrenes. 6: R1 = R2 = H (d); R1 = Me, R2 = H (e); R1 = R2 = Me (f); 7: R1 = H (c), R1 = Me (d); 9: R1 = R2 = H (a);
1 = Me, R2 = H (b); R1 = R2 = Me (c); and 10: R1 = H (a), R1 = Me (b).
R
It means that the imidazolidine type 4 is formed through addition–
elimination sequence but the corresponding imidazoline type 10 is
a result of the competitive elimination–addition pathway.
The NMR tubes (5 mm) were used for the monitoring of the
reactions. The amount of each species was determined by
integration of the corresponding fluorine signal (with an error of
ꢁ1%). A solution of styrene 1 (0.1–0.4 mmol) and amine (or diamine)
(0.6–4.0 mmol) in MeOH (or without solvent) was prepared and
added to NMR tube. The 19F NMR spectra were detected immediately
after mixing. The time of each experiment depended on the reaction
rate. The spectra obtained were analyzed in comparison with the
spectra of pure compounds.
3. Conclusions
The mechanism of the reaction of trifluoromethylated styrenes
1 with amines was studied. We found that the nature of the
principle intermediates and the sequence of reaction steps
involving in adduct (Ad–E) or alkyne derivative formation (E–
Ad) were elucidated. Providing the direct evidence for two
different multistep mechanisms of nucleophilic vinylic substitu-
tion of halostyrenes 1, this investigation allowed the understand-
ing of influence of the nature of aromatic substituent on the course
of their reaction with nitrogen nucleophiles. It was unambiguously
determined that the acetylene 5 and enamine 6 are the key
intermediates in the synthesis of vinylogous amidinium salts
(primary and secondary amines) or imidazolines (diamines). In
contrast, nucleophilic substitution in EWG styrenes occurs via
addition–elimination sequence. Thus, the substituent in aromatic
moiety is an original switch of the reaction direction.
4.2. Reaction of
pyrrolidine
b-fluoro-b-trifluoromethylstyrene 1b with
The mixture of styrene 1b (82 mg, 0.35 mmol) and pyrrolidine
(225 mg, 3.5 mmol) in methanol was allowed to stay at room
temperature. When the reaction was completed (control by 19F
NMR), the enamine 2a was isolated by column chromatography
(Silica gel, CHCl3/methanol (95:5)); yield 96 mg (96%). The NMR
spectra of enamine obtained were similar to ones described
previoulsy [6].
4. Experimental
Appendix A. Supplementary data
4.1. General remarks
Supplementary data associated with this article can be found, in
the online version, at.doi:10.1016/j.jfluchem.2011.07.015
19F (376.5 MHz), 1H (400.1 MHz), 13C (101.6 MHz) NMR spectra
were recorded on Bruker AVANCE 400 MHz spectrometers for
solutions in MeOH or without it (in excess of amine). Chemical
References
shifts (d) in ppm are reported using a capillary with chloroform-d
[1] For the fundamental reviews, see:
(7.25 for 1H) and trifluoroacetic acid (ꢀ76.0 for 19F) as external
references. The coupling constants (J) are given in Hertz. The
concerted application of 1H–1H 2D homonuclear experiments
COSY [13] and NOESY [14] as well as 1H–13C 2D heteronuclear
experiments HSQC [15] and HMBC [16] were used for the
distinction of the carbon and proton resonances. The silica gel
used for flash chromatography was 230–400 Mesh. All reagents
were of reagent grade and were used as such or distilled prior to
use. All the solvents were dried according to standard procedures
and freshly distilled prior to use.
(a) C.F. Bernasconi, Z. Rappoport, Acc. Chem. Res. 42 (2009) 993–1003;
(b) Z. Rappoport, Recl. Trav. Chim. Pays-Bas 104 (1985) 309–349;
(c) Z. Rappoport, Acc. Chem. Res. 14 (1981) 7–15;
(d) G. Okuyama, G. Lodder, Adv. Phys. Org. Chem. 37 (2002) 1–56;
(e) D. Cohen, R. Bar, S.S. Shaik, J. Am. Chem. Soc. 108 (1986) 231–240;
(f) B.A. Shainyan, Russ. Chem. Rev. 55 (1986) 511–530;
(g) G. Modena, Acc. Chem. Res. 4 (1971) 73–80.
[2] For reviews, see:
(a) A.Yu. Rulev, Usp. Khim. 67 (1998) 317–332;
Russ. Chem. Rev. 67 (1998) 279–293;
(b) A.Yu. Rulev, Usp. Khim. 71 (2002) 225–254;
Russ. Chem. Rev. 71 (2002) 195–221.
[3] (a) A.Yu. Rulev, J. Maddaluno, J. Phys. Org. Chem. 15 (2002) 590–598;
(b) A.Yu. Rulev, S.V. Fedorov, Yu.A. Chuvashov, M.G. Voronkov, Zh. Org. Khim. 39
(2003) 691–694;
b
-Fluoro-, b-chloro- and b-bromo-b-trifluoromethylstyrenes
1a–c were prepared as reported previously [17]. All calculations
were performed for gas phase at MP2/6-311+G(d,p) level using
Firefly QC package [18], which is partially based on the GAMESS
(US) [19] source code.
(c) A.Yu. Rulev, I.A. Ushakov, V.G. Nenajdenko, E.S. Balenkova, M.G. Voronkov,
Eur. J. Org. Chem. (2007) 6039–6045;
(d) A.Yu. Rulev, I.A. Ushakov, V.G. Nenajdenko, Tetrahedron 64 (2008)
8073–8077.

950
A.Y. Rulev et al. / Journal of Fluorine Chemistry 132 (2011) 945–950
[8] V.G. Nenajdenko, V.M. Muzalevskiy, A.V. Shastin, E.S. Balenkova, E.V. Kondrashov,
[4] (a) W. Dmowski, J. Fluorine Chem. 26 (1984) 379–394;
´
´
(b) J.P. Begue, D. Bonnet-Delpon, D. Bouvet, M.H. Rock, J. Chem. Soc. Perkin Trans.
I.A. Ushakov, A.Yu. Rulev, J. Org. Chem. 75 (2010) 5679–5688.
[9] (a) J.E. Huhee, J. Phys. Chem. 70 (1966) 2086–2092;
(b) W. Adcock, A.N. Abeywickrema, J. Org. Chem. 47 (1982) 2957–2966;
(c) R.W. Taft, J. Phys. Chem. 64 (1960) 1805–1815;
1 (1998) 1797–1800;
(c) B. Jiang, F. Zhang, W. Xiong, Tetrahedron 58 (2002) 261–264;
(d) V.M. Muzalevskiy, A.V. Shastin, E.S. Balenkova, G. Haufe, V.G. Nenajdenko,
Russ. Chem. Bull. 57 (2008) 2217–2219;
(d) S. Chandra, Tetrahedron 22 (1966) 3403–3407.
(e) V.M. Muzalevskiy, V.G. Nenajdenko, A.V. Shastin, E.S. Balenkova, G. Haufe,
Tetrahedron 65 (2009) 7553–7561;
[10] For the recent review on aza-Michael and anti-aza-Michael reaction, see:
A.Yu. Rulev, Usp. Khim. 80 (2011) 211–233;
(f) A.Yu. Rulev, I.A. Ushakov, J. Fluorine Chem. 131 (2010) 53–58;
(g) N.N. Chipanina, T.N. Aksamentova, B.A. Shainyan, A.Yu. Rulev, J. Mol. Struct.
(THEOCHEM) 947 (2010) 22–31.
A.Yu. Rulev, Russ. Chem. Rev. 80 (2011) 197–218.
[11] A.Yu. Rulev, A.S. Mokov, L.B. Krivdin, N.A. Keiko, M.G. Voronkov, Magn. Reson.
Chem. 35 (1997) 533–537, and references therein.
[5] For the recent reviews, see:
[12] V.M. Muzalevskiy, V.G. Nenajdenko, A.V. Shatin, E.S. Balenkova, G. Haufe, Synthe-
sis (2009) 2249–2259.
(a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, Wiley-VCH, Weinheim, 2004;
(b) M. Schlosser, Angew. Chem. Int. Ed. 45 (2006) 5432–5446;
(c) Fluorinated heterocycles, in: A.A. Gakh, K.L. Kirk (Eds.), ACS Symposium Series
1043, Oxford University Press, New York, 2009.
(d) V. Petrov (Ed.), Fluorinated Heterocyclic Compounds. Synthesis, Chemistry
and Applications, John Wiley & Sons, New York, 2009;
(e) V.M. Muzalevskiy, A.V. Shastin, E.S. Balenkova, G. Haufe, V.G. Nenajdenko,
Synthesis (2009) 3905–3929;
[13] K. Nagayama, A. Kumar, K. Wu¨thrich, R.R. Ernst, J. Magn. Reson. 40 (1980) 321–334.
[14] J. Jeener, B.H. Meier, P. Bachmann, R.R. Ernst, J. Chem. Phys. 71 (1979) 4546–4553.
[15] A. Bax, S. Subramanian, J. Magn. Reson. 67 (1986) 565–569.
[16] A. Bax, M.F. Summers, J. Am. Chem. Soc. 108 (1986) 2093–2094.
[17] (a) A.A. Goldberg, V.M. Muzalevskiy, A.V. Shastin, E.S. Balenkova, V.G. Nenaj-
denko, J. Fluorine Chem. 131 (2010) 384–388;
(b) V.N. Korotchenko, A.V. Shastin, V.G. Nenajdenko, E.S. Balenkova, Tetrahedron
57 (2001) 7519–7527;
(f) V.G. Nenajdenko, A.L. Krasovskiy, E.S. Balenkova, Tetrahedron 63 (2007)
12481–12539;
(c) V.G. Nenajdenko, G.N. Varseev, A.V. Shastin, E.S. Balenkova, J. Fluorine Chem.
126 (2005) 907–913;
(g) S.V. Druzhinin, E.S. Balenkova, V.G. Nenajdenko, Tetrahedron 63 (2007)
7753–7808.
(d) V.G. Nenajdenko, V.N. Korotchenko, A.V. Shastin, E.S. Balenkova, Russ. Chem.
Bull. 53 (2004) 1034–1064.
[6] V.M. Muzalevskiy, V.G. Nenajdenko, A.Yu. Rulev, I.A. Ushakov, G.V. Roma-
nenko, A.V. Shastin, E.S. Balenkova, G. Haufe, Tetrahedron 65 (2009)
6991–7000.
[7] A.Yu. Rulev, V.M. Muzalevskiy, E.V. Kondrashov, I.A. Ushakov, A.V. Shastin, E.S.
Balenkova, G. Haufe, V.G. Nenajdenko, Eur. J. Org. Chem. (2010) 300–310.
[18] A. Granovsky, Firefly Version 7.1.G, http://classic.chem.msu.su/gran/firefly/
index.html.
[19] M.W. Schmidt, K.K. Baldridge, J.A. Boatz, S.T. Elbert, M.S. Gordon, J.H. Jensen, S.
Koseki, N. Matsunaga, K.A. Nguyen, S. Su, T.L. Windus, M. Dupuis, J.A. Montgom-
ery, J. Comput. Chem. 14 (1993) 1347–1363.