Experimental and Theoretical Study of an Intramolecular CF3-Group Shift in the Reactions of α-Bromoenones with 1,2-Diamines

Article abstract of DOI:10.1002/chem.201502706

The reactions of trifluoromethylated 2-bromoenones and N,N′-dialkyl-1,2-diamines have been studied. Depending on the structures of the starting compounds, the formation of 2-trifluoroacetylpiperazine or 3-trifluoromethylpiperazine-2-ones was observed. The mechanism of the reaction is discussed in terms of multistep processes involving sequential substitution of bromine in the starting α-bromoenones and intramolecular cyclization of the captodative aminoenones as key intermediates to form the target heterocycles. The results of theoretical calculations are in perfect agreement with the experimental data. The unique role of the trifluoromethyl group in this reaction is demonstrated.

Full text of DOI:10.1002/chem.201502706

DOI: 10.1002/chem.201502706
Full Paper
&
Reaction Mechanisms
Experimental and Theoretical Study of an Intramolecular CF3-
Group Shift in the Reactions of a-Bromoenones with 1,2-Diamines
Vasily M. Muzalevskiy,[a] Yury A. Ustynyuk,[a] Igor P. Gloriozov,[a] Vyacheslav A. Chertkov,[a]
Alexander Yu. Rulev,*[b] Evgeniy V. Kondrashov,[b] Igor A. Ushakov,[b] Alexey R. Romanov,[b]
and Valentine G. Nenajdenko*[a]
Abstract: The reactions of trifluoromethylated 2-bromo-
enones and N,N’-dialkyl-1,2-diamines have been studied.
Depending on the structures of the starting compounds, the
formation of 2-trifluoroacetylpiperazine or 3-trifluoro-
methylpiperazine-2-ones was observed. The mechanism of
the reaction is discussed in terms of multistep processes
involving sequential substitution of bromine in the starting
a-bromoenones and intramolecular cyclization of the capto-
dative aminoenones as key intermediates to form the target
heterocycles. The results of theoretical calculations are in
perfect agreement with the experimental data. The unique
role of the trifluoromethyl group in this reaction is demon-
strated.
systems.[3] However, trifluoromethylated piperazines are a very
rare type of heterocycle, mainly due to the difficulties of their
synthesis.[4]
Introduction
Nitrogen heterocycles are frequently found in nature and are
of great interest to both synthetic and pharmaceutical
chemists.[1] Among them, fluorinated heterocyclic compounds
have a particular value and their chemistry is one of the most
intensively growing areas of research. The incorporation of flu-
orine or perfluoroalkyl groups (as a rule, CF3) into an organic
compound provides a unique mix of physicochemical and bio-
logical properties. As a result, fluorinated compounds have
found widespread applications in the construction of new ma-
terials, agrochemicals, and drugs. For example, about 20–25%
of currently used drugs contain in the structure at least one
fluorine atom or trifluoromethyl group.[2] Significant attention
has been paid to the elaboration of efficient synthetic routes
to fluorinated derivatives bearing both saturated and unsatu-
rated aza rings. a,b-Unsaturated carbonyl compounds as well
as a-halogenated carbonyl derivatives are classical building
blocks for the assembly of various carbo- and heterocyclic
Recently we reported our preliminary results of an unusual
reaction of bromoalkenyl trifluoromethyl ketones with
symmetrically disubstituted ethylenediamines to form the
unexpected trifluoromethylated piperazinones by a 1,2-shift of
the CF3 group.[5] Herein, we would like to present the
complete and generalized results of this reaction, including an
experimental and theoretical study of its mechanism.
Results and Discussion
A series of model bromoenones 1 were prepared in high yields
by the sequential bromination/dehydrobromination of enones
without the isolation of the intermediate dibromo derivatives
(Scheme 1).[6]
A number of symmetrical N,N’-dialkylethylenediamines 2
were synthesized easily by the reaction of 1,2-dibromoethane
[a] Dr. V. M. Muzalevskiy, Prof. Dr. Yu. A. Ustynyuk, Dr. I. P. Gloriozov,
Dr. V. A. Chertkov, Prof. Dr. V. G. Nenajdenko
Department of Chemistry, Moscow State University
Leninskie Gory, Moscow 119992 (Russia)
Fax: (+7)495-932-8846
E-mail: nen@acylium.chem.msu.ru
[b] Dr. A. Yu. Rulev, Dr. E. V. Kondrashov, Dr. I. A. Ushakov, A. R. Romanov
A. E. Favorsky Institute of Chemistry
Siberian Branch of the Russian Academy of Sciences
1, Favorsky Str., Irkutsk 664033 (Russia)
Fax: (+7)3952-419346
E-mail: rulev@irioch.irk.ru
Supporting information for this article, containing all experimental details,
characterization data, copies of NMR spectra, and the results of kinetic and
theoretical study (DFT and MP2 calculations), is available on the WWW
under http://dx.doi.org/10.1002/chem.201502706.
Scheme 1. Synthesis of the starting materials 1 and 2.
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with the corresponding aliphatic amines[7] or by the reductive
amination
(Scheme 1).[8]
of
benzaldehyde
with
ethylenediamine
It was demonstrated that the reaction of bromoenone 1a
with N,N’-dimethylethylenediamine (DMEDA) resulted in forma-
tion of unexpected 3-trifluoromethyl-piperazine-2-ones, the
formation of which is a result of skeletal rearrangement with
migration of the trifluoromethyl group in adjacent position.[5]
Predictable 2-acyl piperazines[9] were not formed. The best re-
sults (yields up to 87%) were obtained when trifluoroethanol
(TFE) was used as a solvent in presence of Et3N as a base
(instead of second equivalent of DMEDA). The reaction was
found to be very general to afford trifluoromethylated pipera-
zinones 3 in good to high yields. (Scheme 2) The structures of
Figure 1. Reaction profiles for the interaction of 1a with DMEDA.
ical shift of this component was unexpectedly found to be at
a high field (d=137 ppm), which is typical of CF2 groups.[11]
Analysis of the seven-component reaction profile curves in
terms of the kinetic mechanism is presented in Figure 1.
Unfortunately the presence of so many relatively short-lived
intermediates made their precise structural elucidation barely
possible.
Scheme 2. The reaction of diamines with CF3-bromoenones 1.
In contrast, in the case of the reaction of 1b in CDCl3 we ob-
served a more simple situation. After 1.5 h of reaction, the sig-
nals of one principal intermediate (d=À80.3 ppm) as well as
the final heterocycle 3b (d=À66.4 ppm) were detected in the
19F NMR spectrum of the reaction mixture. Careful analysis of
the multinuclear NMR data allowed us to conclude that the in-
termediate has a structure of piperazinol 5 (see Scheme 3).
Indeed, a singlet at d=5.92 ppm in the 1H NMR spectrum
points to an olefinic proton and the signal of a quaternary
carbon atom (quartet, d=86.9 ppm, JCF =30.1 Hz) in the
13C NMR spectrum corresponds to a C(OH)CF3 moiety. Finally,
two types of amine nitrogen atoms (d=À332.8 and
À342.6 ppm) were detected in the 15N NMR spectrum. As the
reaction progressed, the signal intensity of this intermediate
decreased and the intensity of characteristic signals of the final
product 3b simultaneously increased. In addition, piperazinone
3b was isolated in good yield as the only product after
column chromatography of the reaction mixture. All these
facts indicate that piperazinol 5 is the precursor of piperazi-
none 3b.
The proposed cascade mechanism for the formation of pi-
perazinol 5 is given in Scheme 3. It has previously been report-
ed that the reaction of bromoenones 1 with secondary amines
leads to indenols 6 over several steps.[6] First, the nucleophilic
substitution of bromine proceeds by an aza-Michael addition/
nucleophilic substitution/elimination sequence, which is
generally accepted for gem-activated haloalkenes.[3a] Next, in-
tramolecular electrophilic aromatic substitution occurs to give
6 (Scheme 3). It seems reasonable to assume that the forma-
tion of the intermediate piperazinol 5 occurs by the same
pathway. In the first step, the nucleophilic substitution of bro-
mine gives aminoenone H via intermediates E and F. In this
compounds 3 were elucidated unambiguously using a combi-
nation of various NMR methods; the ultimate confirmation of
the structures was achieved by X-ray diffraction analysis of
3g.[5]
Next, we investigated the reaction mechanism. First, the re-
action of bromoenone 1a with DMEDA in TFE in an NMR tube
was monitored by 19F NMR spectroscopy. Under these condi-
tions the only product was obtained in high yield (84% by
19F NMR) in a few hours.[5] In this work we evaluated the kinet-
ics of the process by 19F NMR spectroscopy, and numerical
analysis of the reaction profiles of the reactant, product, and
intermediates was carried out by using the DYNAFIT program
(see the Supporting Information for details).[10] In just a short
time (200–300 s) after mixing of the reactants, the 19F NMR
spectra showed plenty of intermediate species as individual
components on the NMR timescale (Figure 1).
At this time, three of these intermediates had relative molar
fractions higher than 20%. Another ten minor intermediates
had a combined molar fraction of around 20% at this
moment. All these components reveal reaction profile curves
with characteristic half-reaction times in the range of 500 to
2000 s. The major product 3a had an abundance of 82.0 mol%
after approximately 100 min. The maximum abundance of the
product was observed at around 3 h after mixing. The molar
fractions of the intermediate components B (peak at d=
À73.83 ppm) and C (peak at d=À75.36 ppm) were negligible
after 6 hours, whereas, in contrast, intermediate components A
(peak at d=À69,0 ppm) and minors retained a significant
equilibrated abundance until the endpoint of the experiment
(2.2 and 5.4 mol%, respectively). In addition, the product D
had an abundance of 8.9 mol% at the endpoint. The 19F chem-
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Scheme 4. Shift of C2F5 group to form 7 from 1 f.
Scheme 3. Possible mechanism for the reaction of 1b with DMEDA.
case it is the second nitrogen nucleophilic center of the ethyle-
nediamine moiety (not aromatic carbon atom) that attacks the
carbonyl carbon. This intramolecular cyclization of captodative
aminoenone H leads directly to piperazinol 5, which has
a rather acidic hydroxy group due to the presence of the CF3
group. The quite basic nature of the piperazine nitrogen favors
intramolecular proton transfer to form the corresponding imi-
nium salt G. Finally, a 1,2-shift of the trifluoromethyl group as
internal nucleophile to the iminium electrophilic center occurs
to give the target piperazinone 3. According to this scheme,
polar protic solvents would be favorable for the process. Being
at least 1000 times more acidic then other alcohols (pKa =12.5
in water), trifluoroethanol has a well-tuned balance of acidity
and polarity, which provides higher yields of the target hetero-
cycle 3.[12] At the same time, hexafluoroisopropanol is probably
too acidic (pKa =9.3), thereby resulting in a significant decrease
of the product yield (19%).
Scheme 5. Fragmentation in the reactions of non-fluorinated enones with
DMEDA.
In contrast, less electrophilic non-fluorinated a-bromo-a,b-
unsaturated carbonyl compounds reacted with DMEDA by
a different pathway. Thus, when bromoenal 1g was treated
with DMEDA, only cyclic aminal 8 was formed as the principal
reaction product (according to the GC-MS analysis; Scheme 5).
This compound was isolated in crude form contaminated with
PhCHO due to partial hydrolysis on silica gel during column
chromatography. Its structure was undoubtedly confirmed by
a perfect match of its 1H and 13C NMR data with those reported
in the literature.[13] In the case of non-fluorinated bromoenones
1h–j, the same destructive cleavage of the double bond takes
place. A few years ago we described a similar fragmentation of
trifluoromethylated haloalkenes and alkynes to derivatives of
carboxylic acids.[14] An analogous fragmentation has recently
been demonstrated for acetylenic ketones by Vasilevsky and
Alabugin and co-workers.[15] In both cases the key step pro-
ceeds via a six-membered transition state and leads to benzoic
acid derivatives as the principal fragmentation products.
The possible mechanism for the formation of benzaldehyde
derivative 8 from non-fluorinated bromoenones is shown in
Scheme 5. First, aza-Michael addition of DMEDA to a-bromo-
enone 1 leads to adduct I, which is transformed into diamine
ketone J by nucleophilic substitution of the bromine with
a second equivalent of DMEDA. Next, a retro-Mannich reaction
occurs to give the iminium salt K and amino ketone derivative
L. The former immediately gives aminal 8 by intramolecular
cyclization. Careful GC-MS analysis of the crude reaction mix-
ture of the reaction of DMEDA with trifluoromethyl-substituted
enones 1 showed that fragmentation also takes place as
a minor side-reaction, however, the principal reaction pathway
was the formation of piperazinone 3. This shift of reactivity can
be explained in terms of the much higher electrophilicity of
the carbonyl group in fluorinated enones preferentially direct-
ing the attack of the amine on the carbonyl moiety. Thus, the
perfluoroalkyl moiety attached to the carbonyl group plays an
important and unique role in all the steps of these unusual
transformations.
Why doesn’t the reaction stop after the formation of the
piperazinol? To answer that question we carried out quantum
chemical calculations of the intramolecular cascade of transfor-
mations of intermediate captodative aminoenone H into
piperazinol 5, followed by its isomerization into piperazinone 3
(see below).
It is very important to note that this mechanism demands
the presence of the carbonyl group joined to a strong
electron-withdrawing moiety. To confirm this proposition, we
evaluated the role of the substituent attached to the carbonyl
group in these unusual transformations. For this purpose, the
reaction of DMEDA with other fluorinated and non-fluorinated
bromoenones was examined.
First, C2F5-bromoenone 1 f was prepared as the Z isomer
starting from b-bromostyrene in good overall yield (see the
Supporting Information). We found that the reaction direction
depends dramatically on the acceptor ability of the substitu-
ent. Trifluoromethyl and pentafluoroethyl groups have a similar
nature in terms of electronic effects, but the pentafluoroethyl
moiety is much more sterically demanding. Therefore, it
should be expected that in both cases the reactions would
occur in the same fashion. Indeed, the treatment of enone 1 f
with DMEDA at room temperature in THF or TFE in the pres-
ence of Et3N smoothly gave the corresponding piperazinone 7
in good yield (Scheme 4).
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To our knowledge, this is the first example of the migration
of a CF3 group to the adjacent carbon atom in a heterocycle.
We found three examples in the literature of a similar shift of
the trifluoromethyl group. A piperazine-derived hemiaminal of
trifluoroacetaldehyde can be used as an anionic trifluoro-
methylating agent, transferring the CF3 fragment in the
presence of tBuOK. This methodology has been used for the
trifluoromethylation of nonracemizable carbonyl compounds,
disulfides, and diselenides.[16] It should be noted that the
piperazine-derived hemiaminal of trifluoroacetaldehyde de-
mands the use of a rather strong base, namely tBuOK. In our
case, the intramolecular transfer of the CF3 group proceeds in
much milder conditions due to the presence of an internal
basic center. Very recently, the first example of an asymmetric
migration of a perfluorinated moiety to a carbonyl group was
published by Tang and co-workers.[17]
Figure 2. Characteristic NMR spectroscopic parameters for piperazines 4.
tra, confirm the presence of the CHÀCH moiety. The values of
3
the JHH coupling constants are 7.9–8.3 Hz, which correspond
to axial positions of both of the CH protons. Consequently,
piperazines 4 have a trans configuration. The presence of the
trifluoroacetyl group is clearly indicated by the quadruplet at d
ꢀ192 ppm (2JCF =34.5 Hz) in the 13C NMR spectra and the sin-
glet at dꢀÀ79 ppm in the 19F NMR spectra. At the same time,
low-field shifted singlets at d=208.6 and 199.3–200.3 ppm in
the 13C NMR spectra point to acetyl and benzoyl groups in
compounds 4.
Why is the behavior of N,N’-dicyclopropylethylenediamine so
different to that of other substituted ethylenediamines in the
same reaction with CF3-bromoenones 1? Evidently, the forma-
tion of 2-trifluoroacetylated piperazines 4 cannot be explained
only in terms of the steric effect of the cyclopropyl group
because isostructural isopropyl- and cyclohexyl-substituted
diamines selectively gave the rearrangement products 3-tri-
fluoromethylpiperazin-2-ones 3.
Rather unpredictable results were obtained when a-bromo-
enones 1 were treated with N,N’-dicyclopropylethylenediamine
in THF. In this case the reaction proceeds highly chemo- and
stereoselectively to give the corresponding acylated pipera-
zines 4b–i in good yields as the only product (Table 1).
Table 1. Reactions of a-bromoenones 1 with N,N’-dicyclopropylethylene-
diamine.
The results observed also cannot be explained in terms of
the basicity of this diamine. It is known that cyclopropylamine
is less basic (pKa =9.0) than other aliphatic amines.[18] However,
the basicity of cyclopropylamine is similar to the basicity of
benzylamine (pKa =9.3, see also Table 2). Nevertheless, in the
Entry
Enone 1
Ar
R
Yield of piperazine 4 [%]
1
2
3
4
5
6
7
8
1a
1b
1d
1e
1 f
1h
1i
Ph
CF3
CF3
CF3
CF3
C2F5
Me
Ph
4b, 60
4c, 63
4d, 57
4e, 69
4 f, 36
4g, 62
4h, 85
4i, 89
4-MeC6H4
3-MeC6H4
3-MeOC6H4
Ph
Ph
Ph
Table 2. Comparison of substituents effects.
1j
Ph
4-NO2C6H4
Substituent R
A value
[kcalmolÀ1
Rotation barrier
RNH2 [kcalmolÀ1
pKa(H2O)
of RNH2
]
]
Me
Et
iPr
cyclohexyl
cyclopropyl
benzyl
1.7
1.75
2.15
2.15
–
1.68
–
–
1.96[a]
2.7
3.1
–
3.44–4.9c]
10.6[b]
10.7
10.6
10.6
9.0
9.3
9.7
10.0
In contrast, the reaction of bromoenone 1a with N,N’-dicy-
clopropylethylenediamine in TFE afforded piperazinone 3l, but
only in 15% yield, which is dramatically low compared with
the reactions of other ethylenediamines in TFE. Thus, we have
finally succeeded in synthesizing piperazines 4. Interestingly, in
contrast to other ethylenediamines, the symmetrically substi-
tuted N,N’-dicyclopropylethylenediamine reacts with both fluo-
rinated (1a,b,d–f) and non-fluorinated bromoenones (1h–j)
similarly to give the acylated piperazines (Table 1). Remarkably,
the reactions proceed 100% stereoselectively to form only the
trans-substituted piperazines 4. It should be noted that
fluorinated piperazines 4b–f, due to the higher activity of the
carbonyl, were isolated along with their hydrated form as an
admixture.
–
allyl
3.7[d]
–
ethylenediamine
[a] See ref. [21]. [b] See ref. [22]. [c] See ref. [23]. [d] See ref. [24].
case of the reaction with benzyl-substituted ethylenediamine,
we observed only the formation of the rearranged product 3h.
Therefore, the influence of the cyclopropyl group is more sig-
nificant and it cannot be explained in terms of nucleophilicity
(basicity) and steric effects. The ability of the cyclopropyl
group to stabilize carbocations and radicals is very well
known.[19] Examples of the conjugation of the cyclopropyl
moiety with electron-rich centers are rare in the literature, and
The structures of piperazines 4 were indubitably determined
1
by NMR analysis (Figure 2). Thus, two doublets in the H NMR
spectra for compound 4d at d=3.56 and 3.95 ppm, as well as
two singlets at dꢀ69 and 70 ppm in the 13C (APT) NMR spec-
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The structures of the isomeric piperazinones 9a (major) and
1
9a’ (minor) were determined by H, 13C, and 19F NMR spectros-
copy as well as by the positions of the cross-peaks in 2D COSY,
HSQC, and HMBC experiments. The starting points for the
structural assignments were the characteristic multiplets of the
monosubstituted benzene and cyclopropane rings in the
1H NMR spectra, as well as the carbonyl and characteristic
quartets of carbons adjacent to CF3 in the 13C NMR spectra.
n
Analysis of the vicinal and geminal JHH coupling constants
n
(see, e.g., refs. [25,26]), as well as the heteronuclear JCH cou-
pling constants (see, e.g., refs. [27]) in the parent cyclic systems
was performed. Analysis of all the NMR data allowed us to con-
clude that the products under investigation were the isomeric
piperazin-2-ones with four substituents, namely methyl and
cyclopropyl moieties attached to the two nitrogen atoms and
the geminally displaced CF3 and Bn groups attached to carbon
at the 3-position (Figure 3).
Scheme 6. Two directions for the reaction enones 1 with ethylenediamines.
experimental confirmation of such conjugation is almost
unknown.[20]
Therefore, we can assume that there is a bifurcation point
on the reaction pathway followed by the formation of either
piperazinone 3 or trifluoroacetylated piperazine 4 (Scheme 6).
In fact, in either case, the aza-Michael addition is the initial
step of all the transformations. Adduct I can further undergo
either intra- or intermolecular nucleophilic substitution leading
directly to trifluoroacetylated piperazine 4 or diamine deriva-
tive J, respectively, with the latter transforming into piperazi-
none 3 over several steps (see the results of the calculations).
In addition, we decided to check our hypothesis concerning
the preferred site of intermolecular substitution by the MeNH
of ethylenediamine in comparison with cyclo-PrNH moiety. For
this we used unsymmetrical N-cyclopropyl-N’-methylethylene-
diamine. This diamine has a more nucleophilic MeNH fragment
and a less reactive cyclo-PrNH moiety. According to our previ-
ous observations, the first step of the reaction with bromo-
enones 1 should be a Michael addition with the participation
of the more nucleophilic methylamino group to form inter-
mediate E (see Scheme 3). Subsequent tandem reaction should
provide the rearrangement product 9 with the cyclopropyl
moiety at the nitrogen close to the carbonyl group. This pre-
diction was confirmed experimentally; the reaction of bromoe-
nones 1 with N-cyclopropyl-N’-methylethylenediamine resulted
in the formation of a mixture of two isomeric piperazinones 9
and 9’, in which isomer 9 dominates (Scheme 7). The formation
of 9 as the major reaction product clearly indicates that the in-
termolecular bromine substitution occurs mainly through the
N-methylated side of the binucleophile.
Figure 3. Sructures and atom numbering of 9a (major, a,b) and 9a’ (minor,
c,d). The arrows indicate selected long-range connectivities: a) nJHH (blue),
b) nJCH (red), c) nJFH (green), and d) nJCH (red).
The relative positions of the methyl and cyclopropyl groups
were unambiguously determined by the multiplicities of the
n
n
signals and the long-range JHF and JCF coupling constants
with the trifluormethyl group, supported by the intense cross-
peaks between the carbonyl carbon and the protons of the
methyl group for isomer 9a’ (minor) and the cyclopropyl
proton Ha for isomer 9a (major) in the 2D HMBC spectra (see
Figure 3b,d).
Theoretical study of the reaction mechanism
Scheme 8 shows the most probable pathway for the
formation of heterocycles 3 and 4 from the reactions
of 2-bromoenones
1 with N,N’-dialkylethylenedi-
amines. To understand better the mechanism and
the driving forces of these transformations, we realiz-
ed DFT and MP2 quantum chemical modeling of the
basic steps in the reactions of N,N’-dimethylethylene-
diamine (R=CH3) and N,N’-dicyclopropylethylenedia-
mine (R=C3H5) with bromoenones 1. The geometries
of all the structures under consideration were com-
pletely optimized for gas-phase conditions by using
Scheme 7. Reaction of an unsymmetrical diamine with bromoenone 1.
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the observed experimental re-
sults. To overcome these restric-
tions it was necessary to take
into account specific solvation
by including solvent molecules
in the system. According to the
calculations, 2,2,2-trifluoroetha-
nol as a proton donor forms
strong hydrogen bonds with the
oxygen atoms of the trifluoro-
acetyl group, thereby substan-
tially increasing their electrophi-
licity. In the SN2 substitution re-
action of the bromine atom
(processes E!9 and E!F),
2,2,2-trifluoroethanol forms a sol-
vate with the leaving bromine to
promote the nucleophilic substi-
tution. This specific solvation
effect can be clearly seen
when comparing the structures
of
the
transition
states
Scheme 8. General mechanistic scheme for the formation of 3 and 4.
TS2a*2CF3CH2OH and TS2 (gas-
phase conditions, Figure 5). The
first principles DFT (GGA PBE functional) with the TZ2p basis
significant shortening of the CÀBr bond (by 0.201 Š) and the
elongation of the CÀN bond (by 0.291 Š) in the reaction center
can be immediately noted. This indicates that the
TS2a*2CF3CH2OH occurs earlier than TS2a. The strong O1À
H···Br hydrogen bond is clearly evident by the short contact
r(H···Br)=2.346 Š. The length of the O1ÀH bond increased by
0.1 Š compared with the equilibrium value for the free mole-
cules of trifluoroethanol, as can be expected. AIM analysis[28]
confirmed the formation of the strong Br···H ÀO1 hydrogen
set and MP2 with the 6-311+G(d,p) basis set for some
structures
(see
the
Supporting
Information
for
details of the calculations). All details of this theoretical study
will be published elsewhere.
The free-energy changes calculated for the most important
steps of the cascade reactions of 2-bromoenones 1 with N,N’-
dialkylethylenediamines leading to the formation of heterocy-
cles 3 and 4 are shown in Figure 4; the values of DG298 calcu-
lated by DFT for gas-phase con-
ditions and on taking into con-
sideration the effects of solvents
(one or two molecules of 2,2,2-
trifluoroethanol or four mole-
cules of water) are presented.
The processes studied are rel-
atively fast at room temperature
under kinetic control and there-
fore the activation barrier of
each stage of the cascade
should not exceed 20 kcalmolÀ1
.
The theoretical calculations pro-
vided data that satisfy this con-
dition by only taking into ac-
count the effects of specific sol-
vation. Using the polarized con-
tinuum model (PCM model),
which takes into account only
the electrostatic effect of the en-
vironment, led to a significant
decrease in the activation barri-
ers of all the stages, but this ap-
Figure 4. Free-energy profile (DG298 [kcalmolÀ1]) for the sequence H!3. Red: gas phase; blue: solvation with one
proach fails to describe correctly or two molecules of 2,2,2-trifluoroethanol (DFT data).
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Figure 5. Comparison of the values of DG298 [kcalmolÀ1] and the geometries of the transition states TS2 and TS3 (a: Me; b: cyclopropyl) for the sequence
E!4 and E!F in the gas phase and solvated with four molecules of water or with two molecules of TFE (DFT data). Red: R=cyclo-Pr; blue: R=Me.
Conclusion
bond by the presence of the bond critical point for HÀBr
(F[BCP(HÀBr)]=0.019, h[BCP(HÀBr)]=À0.018, À0.018, and
0.120). Bond critical points for CÀBr (F[BCP(CÀBr)]=0.049,
h[BCP(CÀBr)]=À0.041, À0.032, and 0.170) and HÀO1
(F[BCP(HÀO1) ]=0.015, h[BCP(HÀO1)]=À0.019, À0.017, and
0.119) are also present (Figure 5; F is the electron density value
in the critical point and h is the Hessian matrix value in the
critical point).
We have found that the reactions of fluorinated and non-
fluorinated a-bromoenones with 1,2-diamines are extremely
sensitive to the structures of both the electrophile and the
nucleophile. 3-Trifluoromethylated piperazine-2-ones 3 were
formed in the reactions with N,N’-dialkylethylenediamines
through an unusual rearrangement, including an intramolecu-
lar 1,2-migration of the CF3 group as the key step.Alternatively
the formation of 2-trifluoroacetyl piperazines 4 was observed
from dicyclopropylethylenediamine. The results of a detailed
computational study of the reaction mechanism gave good
agreement with the experimental results, revealing the
essential role of the solvent in the reaction. The unique role of
the perfluoroalkyl groups in this rearrangement has been
established.
The second trifluoroethanol molecule in TS2a*2CF3CH2OH
acts as a nucleophilic partner in the hydrogen bonding due to
the lone electron pair of the oxygen atom of the hydroxy
group and forms the NÀH···O2 hydrogen bond (r(HÀO2=
2.081 Š; F[BCP(HÀO2)]=0.015, h[BCP(HÀO2)]=À0.019, À0.017,
and 0.119). In the SN2 substitution reaction of the bromine
atom it facilitates the removal of a proton from the attacking
nitrogen atom of the diamine.
The most interesting feature of the overall sequence of
transformations is the distinct difference in the regioselectivity
of the nucleophilic substitution of the bromine in ketone E.
The N,N’-dicyclopropyl derivative E(b) smoothly undergoes in-
tramolecular cyclization to (trifluoroacetyl)piperazine 4, where-
as the dimethyl derivative E(a) and other dialkyl-derived
compounds form 3-trifluoromethylpiperazin-2-ones 3 under
the same conditions. The results of the calculation demon-
strate that in the case of E(b), TFE solvates the compact transi-
tion state TS2(b) significantly better than TS3(b), whereas the
reverse is true for the other dialkyl derivatives. Very reasonable
results were obtained for the rearrangement sequence leading
to piperazinones 3, which are the thermodynamically con-
trolled products. Again, participation of the solvent facilitates
the process significantly.
Acknowledgements
This work was supported by the Russian Foundation for Basic
Research (theoretical study of the reaction mechanism and
NMR monitoring Grant nos. 13-03-00063-a and 13-03-01129-a)
and the Russian Science Foundation (grant no. 14-13-00083,
synthesis of starting materials and final products, experimental
study of the reaction mechanism)). The authors are grateful to
the Joint Supercomputer Center (JSCC, Moscow) and to the
Moscow Supercomputing Center. The authors acknowledge
partial support in the measurement of NMR spectra from M.V.
Lomonosov, Moscow State University Program of Develop-
ment.
Keywords: fluorine · heterocycles · reaction mechanisms ·
rearrangement · substituent effects
Chem. Eur. J. 2015, 21, 16982 – 16989
www.chemeurj.org
16988
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Received: July 10, 2015
Published online on October 6, 2015
Chem. Eur. J. 2015, 21, 16982 – 16989
www.chemeurj.org
16989
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim