Reaction of α-bromo enones with 1,2-diamines. Cascade assembly of 3-(trifluoromethyl)piperazin-2-ones via rearrangement

Article abstract of DOI:10.1021/ol401041f

A facile one-pot synthesis of 3-trifluoromethylated piperazin-2-ones has been achieved by the treatment of trifluoromethyl 2-bromo enones with N,N′-disubstituted ethylenediamines in trifluoroethanol. The mechanism of this unexpected reaction is discussed in terms of multistep processes involving formation of captodative aminoenone as a key intermediate. The unique influence of trifluoromethyl group on the reaction path was demonstrated.

Full text of DOI:10.1021/ol401041f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Reaction of r‑Bromo Enones with
1,2-Diamines. Cascade Assembly
of 3‑(Trifluoromethyl)piperazin-2-ones
via Rearrangement
Alexander Yu. Rulev,*,† Vasiliy M. Muzalevskiy,‡ Evgeniy V. Kondrashov,†
Igor A. Ushakov,† Alexey R. Romanov,† Victor N. Khrustalev,§ and
Valentine G. Nenajdenko*,‡
A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of
Sciences, Irkutsk 664033, Russia, Department of Chemistry, Lomonosov Moscow State
University, 119899 Moscow, Russia, A. N. Nesmeyanov Institute of Organoelement
Compounds, Russian Academy of Sciences, Moscow 119991, Russia
rulev@irioch.irk.ru; nen@acylium.chem.msu.ru
Received April 17, 2013
ABSTRACT
A facile one-pot synthesis of 3-trifluoromethylated piperazin-2-ones has been achieved by the treatment of trifluoromethyl 2-bromo enones with
N,N0-disubstituted ethylenediamines in trifluoroethanol. The mechanism of this unexpected reaction is discussed in terms of multistep processes
involving formation of captodative aminoenone as a key intermediate. The unique influence of trifluoromethyl group on the reaction path was
demonstrated.
Piperazine is a privileged structure for medicinal chem-
istry, and this heterocyclic subunit is incorporated as a
crucial structural motive in several top-selling drugs. As a
result, approximately 10% of all modern drugs contain
piperazine or pyrazine fragments (Figure 1). For example,
Abilify (aripiprazole), Seroquel (quetiapine), and Zyprexa
(olanzapine) are very popular modern antipsychotics.
These three drugs alone had near $15 billion in worldwide
sales in 2011.1 It should be emphasized that very wide types
of physiological activity have been demonstrated for
piperazine derivatives including antineoplastics, DPP-IV
inhibitors (diabetes treatment), drugs for erectile dysfunc-
tion treatment, antibiotics, angiogen-II antagonists. There-
fore, development of new approaches to piperazine core
synthesis is a top priority task for modern synthetic
chemistry.
At the same time, much attention has been paid to the
synthesis of fluorinated heterocycles.2 It is not surprising
because it is well recognized that the incorporation of
fluorine atoms or perfluoroalkyl groups into bioactive
molecules leads tothe dramatic modification of its physical
and chemical properties, increased biological activity, and
significantly improves metabolic stability. Therefore,
(2) For recent reviews, see: (a) Fluorinated Heterocyclic Compounds:
Synthesis, Chemistry, and Applications; Petrov, V. A., Ed.; Wiley:
Hoboken, 2009; 515 pp. (b) Fluorinated Heterocycles; Gakh, A. A., Kirk,
K. L., Eds.; ACS Symposium Series; Oxford University Press/American
Chemical Society: Washington, D.C., 2009; 360 pp. (c) Muzalevskiy, V. M.;
Nenajdenko, V. G.; Shastin, A. V.; Balenkova, E. S.; Haufe, G. Synthesis
2009, 3905. (d) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432.
(e) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214.
(f) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications; Wiley-VCH: Weinheim, 2004; 308 pp. (g) Muzalevskiy,
V. M.; Shastin, A. V.; Balenkova, E. S.; Haufe, G.; Nenajdenko, V. G.
Synthesis 2009, 3905. (h) Serdyuk, O. V.; Muzalevskiy, V. M.; Nenajdenko,
V. G. Synthesis 2012, 2115.
† A. E. Favorsky Institute of Chemistry.
‡ Lomonosov Moscow State University.
§ A. N. Nesmeyanov Institute of Organoelement Compounds.
(1) McGrath, N. A.; Brichacek, M.; Njardarson, Jon T. J. Chem.
Educ. 2010, 87, 1348.
r
10.1021/ol401041f
XXXX American Chemical Society

incorporation of fluorine (usually CF3 group or fluorine
atom(s)) is a powerful tool ofmoderndrug designand drug
discovery.3
Starting bromo enones 1aꢀe were prepared in high yields
from R,β-unsaturated CF3ketones by the classical brominationꢀ
dehydrobromination sequence without isolation of the inter-
mediate dibromo derivatives (Scheme 1).6
Scheme 1. Synthesis of Starting Bromo Enones 1aꢀe
First, the model reaction of enone 1a with N,N0-
dimethylethylenediamine (DMEDA) was investigated. We
envisioned that this reaction proceeds as a cascade Michael
additionꢀnucleophilic substitution process to give trifluoro-
acetylated piperazine 2. However, the reaction of enone 1a
with DMEDA surprisingly afforded compound 3a, having
a skeleton of 3-(trifluoromethyl)piperazin-2-one.
Figure 1. Some piperazine-derived drugs.
R,β-Unsaturated carbonyl compounds (enones, enals,
esters) are classical scaffolds for reactions with nucleo-
philes and binucleophiles. They have been studied inten-
sively for the synthesis of various carbo- and heterocyclic
systems.4 CF3 enones are of special interest because they are
very valuable building blocks for the preparation of various
trifluoromethylated heterocycles.5 The reactivity of CF3
enones often differs significantly from nonfluorinated ana-
logues in exhibiting the unique role of fluorine. For example,
we have found unusual reaction of R-bromoalkenyl trifluo-
romethyl ketones with secondary amines leading easily to
captodative carbonyl-bearing aminoalkenes which are read-
ily transformed into indenol derivatives6 in contrast to their
nonfluorinated analogues.7 On the other hand, the capto-
dative formyl(amino)alkenes undergo surprising transfo-
rmations upon treatment with mono- and binucleophiles.8
Considering the significance of both the trifluoromethyl
group and piperazine moiety, we decided to investigate the
reaction of trifluoromethyl R-bromo enones with symme-
trically substituted ethylenediamines as a short pathway to
trifluoroacetylated piperazines.
Table 1. Reaction of Enone 1a with DMEDA
entry
solvent
Et2O
base
yielda (%)
1
DMEDA
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
42
51
25
19
84
8
2
Et2O
3
EtOH
4
(CF3)2CH(OH)
CF3CH2OH
Pyridine
DMSO
DMF
5
6
(3) Selected publications: (a) Filler, R.; Kobayashi, Y.; Yagulpolskii,
L. M. Organofluorine Compounds in Medicinal Chemistry andBiomedical
Applications; Elsevier: Amsterdam, 1993. (b) Fluorine-Containing Amino
Acids. Synthesis and Properties; Kukhar, V. P., Soloshonok, V. A., Eds.;
John Wiley & Sons: Chichester, 1995. (c) Hiyama, V. A. Organofluorine
Compounds: Chemistry and Properties; Springer-Verlag: Berlin, 2000;
Chapter 5, pp 137ꢀ182. (d) Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
(4) For reviews, see: (a) Rulev, A. Yu Russ. Chem. Rev. 1998, 67, 279.
7
18
18
30
20
36
59
50
6
8
9
acetone
CH2Cl2
THF (ꢀ20 °C)
THF
10
11
12
13
14
15
16
ꢀ
MeCN
(b) De Kimpe, N.; Verhe, R. The Chemistry of R-Haloketones,
R-Haloaldehydes and R-Haloimines; Patai, S., Rappoport, Z., Eds.; Wiley:
New York, 1988. For examples, see: (c) Rulev, A. Yu.; Maddaluno, J. J. Phys.
Org. Chem. 2002, 15, 590. (d) Rulev, A. Yu.; Azad, S.; Kotsuki, H.;
Maddaluno, J. Eur. J. Org. Chem. 2010, 6423.
Et3N
PhH
24
0
H2O
(5) (a) Nenajdenko, V. G.; Sanin, A. V.; Balenkova, E. S Molecules
1997, 2, 186. (b) Nenaidenko, V. G.; Sanin, A. V.; Balenkova, E. S. Russ.
Chem. Rev. 1999, 68, 437. (c) Druzhinin, S. V.; Balenkova, E. S.;
Nenajdenko, V. G. Tetrahedron 2007, 63, 7753. (d) Nenajdenko,
V. G.; Balenkova, E. S. ARKIVOC 2011, 246.
(6) Rulev, A. Yu.; Ushakov, I. A.; Nenajdenko, V. G.; Balenkova,
E. S.; Voronkov, M. G. Eur. J. Org. Chem. 2007, 6039. Rulev, A. Yu.;
Ushakov, I. A.; Nenajdenko, V. G. Tetrahedron 2008, 64, 8073.
(7) Rulev, A. Yu. Russ. Chem. Rev. 2002, 71, 195.
(8) (a) Rulev, A. Yu.; Larina, L. I.; Keiko, N. A.; Voronkov, M. G.
J. Chem. Soc., Perkin Trans. 1 1999, 1567. (b) Rulev, A. Yu.; Larina,
L. I.; Voronkov, M. G. Tetrahedron Lett. 2000, 41, 10211. (c) Rulev, A.
Yu.; Larina, L. I.; Voronkov, M. G. Russ. J. Gen. Chem. 2001, 71, 1891.
(d) Rulev, A. Yu.; Larina, L. I.; Voronkov, M. G. Molecules 2001, 6, 892.
(e) Rulev, A. Yu.; Novokshonov, V. V.; Chuvashev, Yu. A.; Fedorov,
S. V.; Larina, L. I. Mendeleev Commun. 2003, 23.
a 19F NMR yields (rt, 48 h).
Deep structural changes are observed for the product 3a
having the trifluoromethyl group migrated in the adjacent
position. This type of compounds is a rare type of hetero-
cycles which is difficult to prepare. To the best of our
knowledge only two approaches to CF3 substituted piper-
azines (based on the trifluoropyruvic acid derivatives9 or
(9) Saloutin, V. I.; Piterskikh, I. A.; Pashkevich, K. I.; Kodess, M. I.
Bull. Acad. Sci. USSR 1983, 32, 2312.
B
Org. Lett., Vol. XX, No. XX, XXXX

corresponding aldehydes10) have been described so far in
the literature.
These binucleophiles were easily prepared by the
reactions of 1,2-dibromoethane with the corresponding
aliphatic amines11 or by using reductive amination of
benzaldehyde with ethylenediamine.12 We have found
that the reaction also proceeded effectively as well with
the formation of trifluoromethylated piperazinones
3fꢀk. The best yields of piperazinones 3fꢀk were
obtained for the more bulky cyclohexyl and isopropyl
substituents (Table 3).
To find optimal reaction conditions, we performed the
reaction in solvents of a different nature and polarity
(Table 1). One can see that the yield depends very signi-
ficantly on the solvent used. Finally, trifluoroethanol was
found to be the solvent of choice providing highest yield of
the product.
The structure of unexpected heterocycles 3aꢀk was
assigned on the basis of multinuclear 1D (1H, 13C, 15N, 19F)
and 2D NMR and IR spectroscopy, mass spectrometry,
Table 2. Reaction of Enones 1a-e with DMEDA
1
and elemental analysis. Thus, both H and 13C NMR
spectra revealed the absence of any signals in the region of
olefinic protons or carbons. In contrast, a pair of diaster-
eotopic protons was observed at 3.00ꢀ3.55 ppm in the 1H
NMR spectra, confirming the presence of the ArCH2
moiety connected to an asymmetric carbon. The car-
bonyl group resonated as a singlet (not a quadruplet
expected for trifluoroacetyl piperazine 2) at 163ꢀ165 ppm
that is characteristic for amides. The quadruplet at
∼70 ppm (J = 20 Hz) confirmed the presence of qua-
ternary carbon center adjacent to trifluoromethyl group.
The peaks of two nitrogen atoms appeared at ca.
ꢀ355 and ꢀ270 ppm, pointing to the presence of amine
and amide functions. Finally, the structure of piperazi-
nones 3 was unambiguously confirmed by X-ray diffrac-
tion analysis of compound 3g (Figure 2).
entry
Ar
product 3 (yield, %)a
1
2
3
4
5
Ph
3a (80)
3b (78)
3c (58)
3d (75)
3e (73)
4-MeC6H4
2,5-(MeO)2C6H3
3-MeC6H4
3-MeOC6H4
a Isolated yield.
Such an unusual skeletal rearrangement took place in
the case of other enones 1bꢀe as well, giving piperazin-
2-ones 3bꢀe in good to high isolated yields (Table 2).
The reaction proceeds smoothly under mild conditions
(room temperature, without any catalyst). The best results
were obtained when triethylamine was used as an acceptor
of HBr instead of an excessive amount of DMEDA.
Table 3. Reactions of 1a with Symmetric N,N0-Disubstituted
Ethylenediamines
entry
R
yield of product 3a (%)
1
2
3
4
5
6
Et
3f, 75 (77)
3g, 87 (90)
3h, 79 (87)
3i, 85 (92)
3j, 83 (93)
3k, 79 (85)
i-Pr
Bn
cyclohexyl
allyl
MeOCH2CH2
a Isolated yield (yield determined by 19F NMR).
Motivated by the importance of the development of an
original approach to unique piperazinones 3, we next
investigated the scope of the reaction. For this purpose,
bromo enone 1a was treated with various symmetric N,N0-
disubstituted ethylenediamines.
Figure 2. X-ray crystal structure of 3g.
(11) Denk, M. K.; Krause, M. J.; Niyogi, D. F.; Gill, N. K. Tetra-
hedron 2003, 59, 7565.
(12) Massing, U.; Fichert, T. US Patent 229037, 2003.
(10) Jenneskens, L. W.; Mahy, J.; De Brabander-van Berg, E. M. M.;
van der Hoef, I.; Lugtenburg, J. Rec. Trav. Chim. Pays-Bas 1995,
114, 97.
Org. Lett., Vol. XX, No. XX, XXXX
C

In order to understand the mechanism of these unusual
transformations, we have monitored the reaction of
R-bromoenone 1b with DMEDA by NMR. Thus, the
19F NMR spectrum of the reaction mixture registered after
stirring of enone 1b and DMEDA for 1.5 h at room
temperature showed the presence of one principal inter-
mediate (δ = ꢀ80.3 ppm) and the final heterocycle
Scheme 2. Plausible Mechanism of the Reaction
1
3b (δ = ꢀ66.4 ppm). The H NMR spectrum contained
only one singlet in the field of the olefinic protons (δ =
5.92 ppm). In the 13C NMR spectrum instead of the
quadruplet of the carbonyl carbon atom the signal
of quaternary carbon atom C(OH)CF3 (quartet, δ =
86.9 ppm, J= 30.1 Hz) appeared. Finally, 15N NMR spectrum
showed the presence of two types of amine nitrogens
(δ=ꢀ332.8 and ꢀ342.6 ppm). These data allow us to conclude
that the principle intermediate of the cascade transforma-
tions has the structure of piperazinol 5. As the reaction
progresses, the intensity of all peaks of the intermediate 5
decreases, while the intensity of characteristic signals of
final product 3 increases. Finally, only piperazinone 3 was
isolatedingoodyield bycolumn chromatographyfrom the
reaction mixture. These facts indicate clearly that the
intermediate 5 is the precursor of the piperazinone 3.
On the bases of NMR monitoring and literature data
concerning captodative alkenes reactivity, we suggest the
following reaction mechanism (Scheme 2). The first step of
all cascade of transformations is the formation of aminoe-
none 4 which proceeds according to the usual scheme of
nucleophilic vinylic substitution in gem-activated halo-
alkenes and includes the aza-Michael additionꢀnucleophilic
substitutionꢀelimination sequence. The second reaction
step is an intramolecular cyclization of captodative amino-
enone 4 to form piperazinol 5.
cyclization with the formation of intermediate 5 takes
place. As a result, a new type of cascade transformations
is initialized leading finally to rearranged product 3 instead
of formation of the indenol 6.6 The demands for the
presence of the strong electron withdrawing group at
carbonyl fragment, accounts for the unique role of
trifluoromethyl group in this transformation. It should
be also noted that the observed reactivity of fluorinated
bromoenones 1 differs significantly from the behavior
of nonfluorinated acetylenic ketones (having the same
oxidation level) in the reaction with diamines.14
Because of the presence of the CF3 group this inter-
mediate has rather acidic hydroxyl group. In presence of
quite basic piperazine nitrogen the intramolecular proton
transfer takes place to generate the corresponding iminium
salt. Finally, 1,2-shift of the trifluoromethyl group as
internal nucleophile to iminium electrophilic center occurs
to give the target heterocycle 3 (Scheme 2). According to
this scheme, polar protic solvents should facilitate the
process. Probably trifluoroethanol has a well tuned bal-
ance of acidity and polarity providing higher yields of
target products 3.13 This solvent has pKa 12.4 in water,
which is at least 1000 times higher in comparison to other
alcohols. It should be noted that hexafluoro-2-propanol is
most probably too acidic (pKa 9.3) resulting in very low
yield of the product (19%).
In conclusion, an efficient method for building up the
trifluoromethylated piperazine core from corresponding
CF3 bromo enones 1 and N,N0-disubstituted ethylenedi-
amineswas developed. To the best ofour knowledge, this is
the first example of the migration of the CF3 group to an
adjacent carbon atom of the heterocycle. Further applica-
tion of this method for the synthesis of fluorinated hetero-
cyclic compounds is now in progress.
Acknowledgment. This work was supported by the
Russian Foundation for Basic Research (Grant Nos.
13-03-00063-a and 13-03-01129-a) and Russian President
Grant MK-7121.2012.3.
Supporting Information Available. Experimental pro-
cedures, characterization data, and 1H, 13C, and 19F
NMR spectra for all synthesized compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
Thus, the reactions of fluorinated bromo enones 1 with
the secondary amines6 and diamines bearing two second-
ary amino groups proceed in a similar mechanism includ-
ing the formation of captodative aminoenone 4 as the
key intermediate. However, because of the presence of
an additional nucleophilic N-center, chemoselective
(14) Roy, S.; Davydova, M. P.; Pal, R.; Gilmore, K.; Tolstikov,
G. A.; Vasilevsky, S. F.; Alabugin, I. V. J. Org. Chem. 2011, 76, 7482.
(13) Zhdanko, A. G.; Gulevich, A. V.; Nenajdenko, V. G. Tetra-
hedron 2009, 65, 4692.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX