Multichannel Reaction of α-Bromoenones with 1,2-Diamines: Synthesis of 1,4-Diazabicyclo[4.1.0]hept-4-enes by Reaction with N-Unsubstituted 1,2-Diamines

Article abstract of DOI:10.1002/ejoc.201501584

The reaction of 2-bromoenones with N-unsubstituted 1,2-diamines was studied. An easy access to 1,4-diazabicyclo[4.1.0]hept-4-enes was developed. The multistep mechanism of the reaction is discussed. Final conclusions on the influence of the structure of t

Full text of DOI:10.1002/ejoc.201501584

DOI: 10.1002/ejoc.201501584
Full Paper
Nitrogen Heterocycles
Multichannel Reaction of α-Bromoenones with 1,2-Diamines:
Synthesis of 1,4-Diazabicyclo[4.1.0]hept-4-enes by Reaction
with N-Unsubstituted 1,2-Diamines
Vasily M. Muzalevskiy,[a] Alexander Yu. Rulev,*[b] Evgeniy V. Kondrashov,[b]
Alexey R. Romanov,[b] Igor A. Ushakov,[b] Vyacheslav A. Chertkov,[a] and
Valentine G. Nenajdenko*[a]
Abstract: The reaction of 2-bromoenones with N-unsubsti- nism of the reaction is discussed. Final conclusions on the influ-
tuted 1,2-diamines was studied. An easy access to 1,4-diazabi- ence of the structure of the starting 2-bromoenones and 1,2-
cyclo[4.1.0]hept-4-enes was developed. The multistep mecha- diamines on the direction of the reaction are established.
Introduction
among the 200 best-selling small-molecule drugs of 2012 (for
examples, see Figure 1).[2] A very diverse spectrum of physiolog-
The piperazine moiety is a very important structural unit for ical activities has been demonstrated for piperazine derivatives,
medicinal chemistry. Analysis of the structures of drugs ap- which include antineoplastics [Gleevec (Imatinib)], DPP-IV
proved by the US FDA showed that the piperazine core is found inhibitors [diabetes treatment, Januvia (Sitagliptin)], drugs for
as a substructure of 59 marketed drugs [in third place after erectile dysfunction treatment [Viagra (Sildenafil)], antibiotics
pyridine (62) and piperidine (72) in the list of the most fre- (fluoroquinolone family of antibiotics, for example Ciprobay),
quently found nitrogen heterocycles in the structures of ap- and angiogen-II antagonists [Ranexa (Ranolizine)]. The world-
proved drugs].[1] One can also find 13 piperazine derivatives wide sales of three piperazine-derived antipsychotics [Abilify
Figure 1. Examples of piperazine-containing drugs from the 200 best-selling small-molecule drugs in 2012.
[a] Department of Chemistry, Moscow State University,
(Aripiprazole), Seroquel (Quetiapine), and Zyprexa (Olanzapine)]
alone were worth nearly 15 billion dollars in 2011 (Figure 1).
Leninskie Gory, Moscow 119992, Russia
E-mail: nenajdenko@org.chem.msu.ru
Another important trend in modern drug design is the incor-
poration of fluorine or trifluoromethyl groups into target
molecules. The current medicinal chemistry literature shows
that the combination of two structural moieties — a nitrogen
heterocycle and a fluorine-containing group — is the trend in
[b] A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian
Academy of Sciences,
1, Favorsky Str., Irkutsk 664033, Russia
E-mail: rulev@irioch.irk.ru
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501584.
Eur. J. Org. Chem. 2016, 1612–1618
1612
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
drug development.[3] In fact, it is well known that the introduc- study the reaction of bromoenones with other 1,2-diamines.[7]
tion of a fluorine atom or an organofluorine moiety into a bio- Using this approach, we expected to be able to prepare other
logically active molecule has a dramatic influence on its reactiv-
ity, as well as its biological properties, such as membrane per-
meability, and binding to target receptors; it can also have a
blocking effect on metabolic decomposition. Thus, it is not sur-
prising that about 225 fluorinated drugs have been approved
by the FDA since 1955,[4a] and that nearly 25 % of newly synthe-
sized drugs and agrochemicals contain fluorine in their struc-
ture.[3,4]
Readily available CF3-bromoenones are attractive building
blocks for the construction of fluorinated heterocycles. These
compounds have at least two electrophilic sites (Scheme 1),
which opens up the number of possible reaction mechanisms,
and makes the outcome of reactions rather unpredictable. Their
reactions with binucleophiles can proceed as complex domino
sequences beginning with an aza-Michael addition as a first
reaction step. These transformations are known as aza-Michael-
initiated ring-closure processes (aza-MIRC), and they play a key
role in the multistep syntheses of biologically active N-hetero-
cycles and of analogues of natural products.[5]
types of piperazine-derived heterocycles bearing fluorinated
fragments (Scheme 1).
We have previously shown that the reaction of CF3-bromo-
enones 1 with secondary amines represents an easy access to
indenol derivatives, and proceeds through an aza-Michael
addition–substitution–elimination–intramolecular
cyclization
sequence.[7] However, if the same substrates are treated with
diamines such as N,N′-dimethylethylenediamine (DMEDA), the
second amine group attacks the carbonyl carbon to give inter-
mediate 2. The latter then undergoes a 1,2-shift of the CF3
group to finally give piperazinones 3.[6] In the case of N,N′-
dicyclopropyl ethylenediamine, an alternative sequence is
preferable, as confirmed by calculations.[6b] Instead of inter-
molecular nucleophilic substitution to form intermediate B
with a second molecule of diamine, cyclization takes place
through intramolecular nucleophilic substitution of bromine
(Scheme 2).
We have demonstrated the unique nature of fluorinated
bromoenones in this reaction. The reaction of nonfluorinated
bromoenones 1c–1f resulted in the destructive cleavage of the
double bond to form cyclic aminal 5 as the principal reaction
product. This fragmentation is a rare example of C–C bond
cleavage under mild nucleophilic conditions.[8,9] A possible
mechanism for the formation of benzaldehyde derivative 5 is
shown in Scheme 2. The key step of the sequence is a retro-
Mannich reaction giving aminoketone derivative D and iminium
salt C, which are then transformed into aminal 5 by cyclization.
Detailed GC–MS analysis of the reaction mixtures for the reac-
tions with CF3 enones 1a and 1b showed that fragmentation is
a minor side reaction in these cases. The principal reaction
pathway is the formation of piperazinone 3. This shift of reactiv-
ity can be explained in terms of the much higher electrophilic-
Scheme 1. Possible reaction directions.
Recently we found an unusual reaction of CF3-bromoenones
with symmetrically substituted ethylenediamines, which leads
to trifluoromethylated piperazinones rather than trifluoroacet- ity of the carbonyl group in fluorinated enones, which directs
ylated piperazines.[6] To gain more detailed information about the attack of the amine onto the carbonyl moiety preferentially
the scope and the mechanism of this reaction, we decided to
(Scheme 2).
Scheme 2. Reactions of bromoenones with N,N′-substituted ethylenediamines.
Eur. J. Org. Chem. 2016, 1612–1618
www.eurjoc.org
1613
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Results and Discussion
also successfully used in the reaction, and gave compounds 7–
9 in high yields. The reaction of (1R,2R)-1,2-diphenylethane-1,2-
diamine gave a 42:58 mixture of diastereomers 7a and 7b,
while the reactions with trans-1,2-diaminocyclohexane were
more stereoselective, and gave 2:1 (for 8) and 3:1 (for 9) mix-
tures of diastereomeric heterocycles. The relative configurations
of the substituents in the aziridine ring in 7 were determined
by comparison of the 1H NMR spectroscopic data with literature
data (Scheme 4). The coupling constants of the aziridine ring
protons of 7 are 1.6–2.4 Hz, which indicates their trans configu-
ration.[10,11]
To conclude our investigation of the reactions of 2-bromoen-
ones with 1,2-diamines, we examined the reaction with N-un-
substituted 1,2-diamines. In contrast to the behaviour of substi-
tuted derivatives, unsubstituted ethylenediamine reacts with α-
bromo α,ꢀ-unsaturated carbonyl compounds by a different
pathway to form bicyclic piperazine derivatives 6. Three key
steps of this sequence of transformations are: aza-Michael addi-
tion, intramolecular SN2 nucleophilic substitution resulting in
aziridine ring construction, and finally carbonyl condensation.
The corresponding 1,4-diazabicyclo[4.1.0]hept-4-ene derivatives
6 were isolated in good yields for both fluorinated and non-
fluorinated bromoenones (Scheme 3, Table 1). The reaction is
highly stereoselective, and all the heterocyclic products were
isolated as single diastereomers. This means that all the steps
of this cascade reaction are stereoselective.
Scheme 4. Assignment of the configuration of compounds 7a and 7b.
For diastereomeric compounds 7a and 7b, a careful compari-
son with their close analogues 10a and 10b[12] was carried out.
This allowed us to assign the configurations of 7a and 7b
(Scheme 4). By comparing the 1H NMR spectra of these dia-
stereomeric pairs, it is possible to see similar multiplicities,
chemical shifts, and coupling constants for corresponding pro-
tons.
Scheme 3. The reaction of 1 with chiral diamines.
Table 1. Synthesis of 1,4-diazabicyclo[4.1.0]hept-4-enes.
The structures of isomeric compounds 8a (major diastereo-
mer) and 8b (minor diastereomer) were assigned through eluci-
dation of 1H, 13C, and 19F NMR spectra, and cross-peak positions
and multiplicities in two-dimensional COSY, HSQC, and HMBC
experiments. The starting points for the structural assignments
were the characteristic multiplets of the monosubstituted benz-
ene and methyne moieties in the 1H and 13C NMR spectra. Anal-
n
ysis of the multiplets was based on vicinal and geminal JH,H
n
couplings (see, e.g., ref.[13]), as well as heteronuclear JC,H cou-
plings (see, e.g., ref.[14]) in the parent cyclic systems. The com-
plete NMR spectroscopic data set allows us to conclude that
the products under investigation are diastereomeric (Figure 2).
Entry
Enone
Ar
R
6, Yield [%]
3
The characteristic values of the vicinal J3a-H,7a-H coupling
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
4-MeC6H4
Ph
Ph
Ph
Ph
CF3
CF3
H
Me
6a, 49
6b, 53
6c, 48
6d, 79
6e, 77
6f, 72
constants [i.e., 9.2 Hz for 8a (major) and 9.6 Hz for 8b minor
diastereomers] show that the nitrogens retain their trans-di-
equatorial configuration on the cyclohexane ring. The low val-
Ph
3
ues of the vicinal J1-H,1a-H coupling constants, and high values
4-NO2C6H4
3
of the vicinal J1-H,C-7a coupling constants (measured according
The more sterically hindered chiral (1R,2R)-1,2-diphenyl- to ref.[15]) indicate that the 1-H proton is in a trans position
ethane-1,2-diamine and trans-1,2-diaminocyclohexane were relative to 1a-H, and a cis position relative to C-7a. A 2D NOESY
Eur. J. Org. Chem. 2016, 1612–1618
www.eurjoc.org
1614
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
3
of a vicinal JC-1a,OH coupling of 7.3 Hz (DMSO solution, high-
resolution HMBC), and an unexpectedly large long-range cou-
pling of the hydroxyl proton to 1a-H (4J1a-H,OH = 2.7 Hz). In our
opinion, this latter value can be rationalised only for a W-config-
uration of the coupling path. So, the relative configuration of
the stereocenters at C-1, C-1a, and C-2 is rel-(1R,1aS,2S).
Figure 2. Structure and atom numbering for compounds 8a (major) and 8b
n
(minor). Arrows indicate selected long-range connectivities JH,H (blue) and
nJC,H (red).
experiment provided the final point in the assignment of the
structures, revealing strong NOE factors of 7.0 % between the
1-H and 7a-H protons for the major diastereomer, and of 6.4 %
between the 1-H and 3a-H protons for the minor diastereomer.
DFT optimized structures [B3LYP/6-311G(d,p)] support the
closeness of these proton pairs, see Figure 2.
The less nucleophilic ortho-phenylenediamine can also be
involved in this reaction. Thus, 1,1a-dihydroazirino[1,2-a]quin-
oxaline 11 was prepared in 73 % yield by the reaction with
bromoenone 1f at reflux in THF. In contrast, when fluorinated
enones 1a and 1b were treated with the same binucleophile,
the reaction could be stopped at the stage of hemiaminals 12,
which were isolated in high yield (Scheme 5). The presence of
the CF3 group stabilizes these compounds.[16] The isolation of
12 confirms that the reactions of enones 1 with diamines bear-
ing primary amino groups follow the classical sequence, includ-
ing aza-Michael addition, intramolecular nucleophilic substitu-
tion, and attack of the second NH2 group of the diamine onto
the carbonyl group.[5a,17,18]
Figure 3. Structure and atom numbering of compound 12c. Arrows indicate
selected long-range connectivities JH,H (blue) and JC,H (red).
n
n
Finally, we examined the reaction of CF3-bromoenone 1g
with N-methylethylenediamine as a binucleophile bearing both
a primary and a secondary amino group. Unlike the reaction
with ethylenediamine and its derivatives bearing two NH2
groups, in this case, fragmentation of the starting enone took
place. Thus, after the treatment of ketone 1g with N-methyleth-
ylenediamine under the standard reaction conditions, only 4-
methoxybenzaldehyde was isolated in 74 % yield after column
chromatography (Scheme 6). Its formation seems to be similar
to that described for non-fluorinated bromoenones (see
Scheme 2). The isolation of the aldehyde instead of its aminal
can be explained by hydrolysis of the aminal during chromatog-
raphy.
Scheme 6. Degradation of 1g with N-methylethylenediamine.
Conclusions
In conclusion, we have found that the reaction of fluorinated
and non-fluorinated α-bromoenones with 1,2-diamines is ex-
tremely sensitive to the structure of both electrophile and nu-
cleophile. As a result, the reaction can go in four different direc-
tions to form various nitrogen heterocycles (Scheme 7). The
reaction with N-unsubstituted ethylenediamines gives 1,4-di-
Scheme 5. Reaction with o-phenylenediamine.
The configurations of 12c and the whole series of com- azabicyclo[4.1.0]hept-4-enes. 3-Trifluoromethylated piperazine-
pounds 12 were determined by NMR spectroscopy, supported 2-ones are formed in the reaction with N,N′-dialkylethylenedi-
by DFT calculations. DFT-optimized structures [B3LYP/6- amines through an unusual rearrangement, involving an intra-
311G(d,p)] revealed that in contrast to diastereomers 8, the spa- molecular 1,2-migration of a CF3 group as a key step.[6] The
tial structure of the six-membered heterocyclic moiety in com- unique role of the perfluoroalkyl groups in this rearrangement
pounds 12 is strongly flattened, with only C-2 going noticeably was established. In contrast, the reaction of non-fluorinated
out of the C-1a–N-1–C-7a–C-3a–N-3 plane (Figure 3). The bromoenones with N,N′-dialkylethylenediamines results in the
hydroxy group at C-2 thus becomes effectively axial, with the destructive cleavage of the C=C double bond. Finally, reaction
proton orientated away from C-1a (torsion angle H–O–C-2–C- of bromoenones with N,N′-dicyclopropylethylenediamine leads
1a 173°). This configuration is supported by the observation to the formation of piperazin-2-yl ketones.[6b]
Eur. J. Org. Chem. 2016, 1612–1618
www.eurjoc.org
1615
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
5) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –73.4 (d, JH,F = 2.5 Hz)
ppm. IR: ν = 1089, 1135, 1195 (C–F), 1661 (C=N) cm–1. C13H13F3N2
˜
(254.25): calcd. C 61.41, H 5.15, N 11.02; found C 60.95, H 5.17, N
10.68.
(6R*,7S*)-7-Phenyl-3,6-diazabicyclo[4.1.0]hept-2-ene (6c):
Brownish viscous oil (84 mg, 48 %). 1H NMR (400.1 MHz, CDCl3): δ =
2.51 (br. s, 1 H, CH), 2.75–2.82 (m, 1 H, CH2), 2.99–3.11 (m, 1 H, CH2),
3.25–3.30 (m, 1 H, CH2), 3.46 (d, J = 2.1 Hz, 1 H, CH), 3.75–3.80 (m,
1 H, CH2), 7.23–7.32 (m, 5 H, Ph), 8.24 (br. s, 1 H, CH=N) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 39.5 (CH), 39.8 (CH), 40.5 (CH2), 43.7
(CH2), 126.0 (Ph), 127.6 (Ph), 128.4 (Ph), 137.7 (Ph), 160.9 (CH=N)
Scheme 7. Four directions of the reaction of bromoenones with diamines.
ppm. IR: ν = 1609 (C=N) cm–1. HRMS (ESI): calcd. for C11H12N2H+ [M
˜
+ H]+ 173.1073; found 173.1077.
Experimental Section
(6R*,7S*)-5-Methyl-7-phenyl-1,4-diazabicyclo[4.1.0]hept-4-ene
(6d): Brownish powder (147 mg, 79 %), m.p. 186–188 °C. 1H NMR
(400.1 MHz, CDCl3): δ = 2.14 (d, J = 2.4 Hz, 3 H, CH3), 2.44 (d, J =
2.1 Hz, 1 H, CH), 2.66.50–2.74 (m, 1 H, CH2), 3.15 (dd, J = 13.1, J =
5.7 Hz, 1 H, CH2), 3.34 (d, J = 2.1 Hz, 1 H, CH), 3.36–3.43 (m, 1 H,
CH2), 3.64 (dd, J = 16.8, J = 4.6 Hz, 1 H, CH2), 7.20–7.30 (m, 5 H, Ph)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 27.0 (CH3), 38.9 (CH2), 39.7
(CH), 41.1 (CH2), 42.5 (CH), 125.9 (Ph), 127.3 (Ph), 128.2 (Ph), 137.9
General Remarks: 1H, 13C, 15N, and 19F NMR spectra were recorded
with Bruker ARX 300, Bruker AMX 400, Bruker AVANCE 400, and
Bruker AV 600 spectrometers with solutions in CDCl3. Chemical
shifts (δ) in ppm are reported with the use of the residual chloro-
1
form (δ = 7.25 ppm for H, and δ = 77.20 ppm for 13C) as internal
references. Coupling constants (J) are given in Hertz (Hz). IR spectra
were recorded with a Bruker Vertex 70 FTIR spectrometer, and with
a portable Varian 3100 diamond ATR/FTIR spectrometer. GC/MS
analyses were carried out with a Shimadzu GC–MS-QP5050A instru-
ment (EI, 70 eV). ESI-MS spectra were measured with a MicroTof
Bruker Daltonics instrument. The silica gel used for flash chromatog-
raphy was 230–400 mesh. All reagents were of reagent grade, and
were either used as supplied or distilled before use. All solvents
were dried by standard procedures, and were freshly distilled before
use. Diastereomers 7a and 7b as well as 8a and 8b were separated.
Diastereomers 9a and 9b were obtained as a mixture, which was
not separated.
(Ph), 166.1 (C=N) ppm. IR: ν = 1660 (C=N) cm–1. HRMS (ESI): calcd.
˜
for C12H14N2H+ [M + H]+ 187.1230; found 187.1222.
(6R*,7S*)-5,7-Diphenyl-1,4-diazabicyclo[4.1.0]hept-4-ene (6e):
Brownish powder (191 mg, 77 %), m.p. 70–72 °C (Lit.[19] 71–73 °C).
1H NMR (400.1 MHz, CDCl3): δ = 2.91–2.99 (m, 1 H, CH2), 3.07 (d,
J = 2.4 Hz, 1 H, CH), 3.24 (ddd, J = 13.3, J = 6.1, J = 1.9 Hz, 1 H,
CH2), 3.47 (d, J = 2.4 Hz, 1 H, CH), 3.64–3.73 (m, 1 H, CH2), 3.94–4.00
(m, 1 H, CH2), 7.30–7.35 (m, 1 H, Ph), 7.36–7.43 (m, 7 H, Ph), 7.78–
7.81 (m, 2 H, Ph) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 39.2 (CH),
40.5 (CH2), 40.7 (CH), 43.3 (CH2), 125.8 (Ph), 125.9 (Ph), 127.4 (Ph),
128.2 (Ph), 128.3 (Ph), 129.8 (Ph), 137.9 (Ph), 138.7 (Ph), 164.4 (C=N)
ppm.
General Procedure for the Reactions of α-Bromoenones 1 with
Diamines: The appropriate enone (1 equiv.), diamine (1.1 equiv.),
and triethylamine (1.5 equiv.) were mixed in THF (2 mL for 1 mmol).
The mixture was kept at room temperature for 48 h, or at reflux for
4 h (compound 11). After this time, the volatiles were evaporated
in vacuo. The residue was purified by column chromatography (sil-
ica gel; CH2Cl2 for 7; CH2Cl2/MeOH, 30:1 for 6, 8, 11, and 12) to give
the target heterocycles. The following compounds were obtained
according to this procedure.
(6R*,7S*)-5-(4-Nitrophenyl)-7-phenyl-1,4-diazabicyclo[4.1.0]-
hept-4-ene (6f): Brown-yellow powder (212 mg, 72 %), m.p. 121–
122 °C (Lit.[20] 124 °C). 1H NMR (400.1 MHz, CDCl3): δ = 2.86–2.93
(m, 1 H, CH2), 2.99 (d, J = 2.4 Hz, 1 H, CH), 3.29 (ddd, J = 13.4, J =
6.4, J = 1.5 Hz, 1 H, CH2), 3.50 (d, J = 2.4 Hz, 1 H, CH), 3.66–3.74 (m,
1 H, CH2), 3.99–4.03 (m, 1 H, CH2), 7.26–7.30 (m, 1 H, Ph), 7.31–7.37
(m, 4 H, Ph), 7.87 (d, J = 8.9 Hz, 2 H, 4-NO2C6H4), 8.16 (d, J = 8.9 Hz,
2 H, 4-NO2C6H4) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 39.0 (CH),
40.1 (CH2), 40.9 (CH), 43.8 (CH2), 123.6 (Ar), 125.9 (Ar), 126.9 (Ar),
127.1 (Ar), 128.5 (Ar), 137.4 (Ar), 144.1 (Ar), 148.4 (Ar), 162.9 (C=N)
ppm.
(6R*,7S*)-7-Phenyl-5-trifluoromethyl-1,4-diazabicyclo[4.1.0]-
hept-4-ene (6a): Pale yellow oil (117 mg, 49 %). 1H NMR
(400.1 MHz, CDCl3): δ = 2.73–2.83 (m, 1 H, 2-H2), 2.79 (m, 1 H, 6-
H2), 3.37 (dd, J = 6.8, J = 13.7 Hz, 1 H, 2-H2), 3.48 (d, J = 1.6 Hz, 1
H, 7-H), 3.52–3.65 (m, 1 H, 3-H2), 4.04 (dd, J = 4.4, J = 17.6 Hz, 1 H,
3-H2), 7.28–7.41 (m, 5 H, Ph) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
36.6 (C-6), 39.6 (C-2), 40.7 (C-7), 43.6 (C-3), 119.5 (q, JC,F = 277.6 Hz,
5-(4-Nitrophenyl)-2,3,7-triphenyl-1,4-diazabicyclo[4.1.0]hept-4-
ene (7): Obtained as a mixture of diastereomers (42:58; 276 mg,
78 %).
CF3), 126.5 (Co), 128.3 (Cp), 128.8 (Cm), 136.8 (Ci), 157.9 (q, JC,F
34.7 Hz, C-5) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –73.2 (d, JH,F
=
=
rel-(2S,3S,6R,7R)-5-(4-Nitrophenyl)-2,3,7-triphenyl-1,4-diazabi-
cyclo[4.1.0]hept-4-ene (7a): a brownish viscous oil: 1H NMR
(400.1 MHz, CDCl3): δ = 3.02–3.04 (m 2 H, CH), 3.30 (d, J = 9.0 Hz,
1 H, CHPh), 4.71 (d, J = 9.0 Hz, 1 H, CHPh), 6.96–7.02 (m, 2 H, Ph),
7.16–7.24 (m, 8 H, Ph), 7.28–7.42 (m, 5 H, Ph), 8.18 (d, J = 9.0 Hz, 2
H, 4-NO2C6H4), 8.29 (d, J = 9.0 Hz, 2 H, 4-NO2C6H4) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 41.6 (CH), 52.4 (CH), 68.5 (CHPh), 73.2
(CHPh), 123.8 (Ar), 125.9 (Ar), 127.0 (Ar), 127.1 (Ar), 127.4 (Ar), 127.7
(Ar), 127.8 (Ar), 127.9 (Ar), 128.1 (Ar), 128.3 (Ar), 128.7 (Ar), 138.2
(Ar), 140.7 (Ar), 140.8 (Ar), 142.0 (Ar), 149.2 (Ar), 164.2 (C=N) ppm.
HRMS (ESI): calcd. for C29H23N3O2H+ [M + H]+ 446.1863; found
446.1852.
2.6 Hz) ppm. 15N NMR (40.6 MHz, CDCl3): δ = –59.9 (N-4), –345.8
(N-1) ppm. IR: ν = 1091, 1135, 1195 (C–F), 1662 (C=N) cm–1. MS (EI):
˜
m/z (%) = 240 (60) [M]+, 117 (100). 91 (46). C12H11F3N2 (240.23):
calcd. C 60.00, H 4.62, N 11.66; found C 59.85, H 4.61, N 11.56.
(6R*,7S*)-7-p-Tolyl-5-trifluoromethyl-1,4-diazabicyclo[4.1.0]-
hept-4-ene (6b): Pale yellow oil (134 mg, 53 %). 1H NMR
(400.1 MHz, CDCl3): δ = 2.25 (s, 3 H, ArCH3), 2.59–2.68 (m, 1 H, 2-
H2), 2.66 (m, 1 H, 6-H), 3.23 (dd, J = 6.8, J = 13.8 Hz, 1 H, 2-H2), 3.33
(d, J = 2.0 Hz, 1 H, 7-H), 3.39–3.50 (m, 1 H, 3-H2), 3.93 (dd, J = 4.6,
J = 17.8 Hz, 1 H, 3-H2), 7.02–7.11 (m, 4 H, Ar) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 21.2 (ArCH3), 36.6 (C-6), 39.6 (C-2), 40.5 (C-
7), 43.6 (C-3), 119.5 (q, JC,F = 277.6 Hz, CF3), 126.3 (Ar-C-2,6), 129.5 rel-(2R,3R,6R,7R)-5-(4-Nitrophenyl)-2,3,7-triphenyl-1,4-diazabi-
(Ar-C-3,5), 133.7 (Ar-C-1), 138.1 (Ar-C-4), 158.0 (q, JC,F = 34.6 Hz, C- cyclo[4.1.0]hept-4-ene (7b): brown-yellow crystals: m.p. 123–
Eur. J. Org. Chem. 2016, 1612–1618
www.eurjoc.org
1616
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
124 °C. 1H NMR (400.1 MHz, CDCl3): δ = 3.40 (d, J = 1.4 Hz, 1 H,
38.7 (CH), 41.2 (CH), 55.1 (CH), 56.3 (CH), 123.5 (Ar), 126.2 (Ar), 127.3
CH), 3.65 (d, J = 9.9 Hz, 1 H, CHPh), 4.03 (d, J = 1.4 Hz, 1 H, CH), (Ar), 127.7 (Ar), 128.5 (Ar), 138.0 (Ar), 144.5 (Ar), 148.4 (Ar), 162.1 (C=
4.64 (d, J = 9.9 Hz, 1 H, CHPh), 6.88–6.94 (m, 2 H, Ph), 6.96–7.01 (m, N) ppm. IR: ν = 1350, 1525 (NO2), 1600 (C=O) cm–1. HRMS (ESI):
˜
2 H, Ph), 7.15–7.29 (m, 6 H, Ph), 7.34–7.49 (m, 5 H, Ph), 8.11 (d, J =
8.9 Hz, 2 H, 4-NO2C6H4), 8.29 (d, J = 8.9 Hz, 2 H, 4-NO2C6H4) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 40.3 (CH), 42.4 (CH), 61.6 (CHPh),
62.0 (CHPh), 126.6 (Ar), 127.1 (Ar), 127.5 (Ar), 127.6 (Ar), 127.9 (Ar),
128.1 (Ar), 128.2 (Ar), 128.3 (Ar), 128.4 (Ar), 128.8 (Ar), 137.0 (Ar),
139.7 (Ar), 141.3 (Ar), 143.9 (Ar), 148.9 (Ar), 162.9 (C=N) ppm. HRMS
(ESI): calcd. for C29H23N3O2H+ [M + H]+ 446.1863; found 446.1851.
calcd. for C21H21N3O2H+ [M + H]+ 348.1707; found 348.1703.
(1S*,1aS*)-2-(4-Nitrophenyl)-1-phenyl-1,1a-dihydroazirino[1,2-
a]quinoxaline (11): Orange-yellow crystals (250 mg, 73 %), m.p.
1
139–140 °C. H NMR (400.1 MHz, CDCl3): δ = 3.04 (s, 1 H, CH), 3.43
(s, 1 H, CH), 7.23–7.51 (m, 10 H, Ph), 8.11 (d, J = 8.6 Hz, 2 H, 4-
NO2C6H4), 8.28 (d, J = 8.6 Hz, 2 H, 4-NO2C6H4) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 39.5 (CH), 43.6 (CH), 123.7, 125.6, 126.2,
126.5, 127.7, 128.0, 128.8, 129.8, 130.1, 136.1, 137.0, 137.7, 142.3,
149.1 (Ar), 158.0 (C=N) ppm. HRMS (ESI): calcd. for C21H15N3O2H+
[M + H]+ 342.1237; found 342.1234.
1-Phenyl-2-(trifluoromethyl)-1,1a,3a,4,5,6,7,7a-octahydro-
azireno[1,2-a]quinoxaline (8): Obtained as a mixture of diastereo-
mers (65:35; 221 mg, 75 %).
rel-(1S,1aR,2R)-1-Phenyl-2-(trifluoromethyl)-1,1a,2,3-tetra-
hydroazireno[1,2-a]quinoxalin-2-ol (12a): Pale yellow solid
(208 mg, 68 %), m.p. 135–136 °C. 1H NMR (400.1 MHz, [D6]acetone):
δ = 3.04 (m, 1 H, 1a-H), 3.57 (m, 1 H, 1-H), 5.90 (br. s, 1 H, NH), 6.45
(s, 1 H, OH), 6.73–6.80 (m, 1 H, 6-H), 6.87–6.92 (m, 1 H, 4-H), 6.96–
7.02 (m, 1 H, 5-H), 7.27–7.31 (m, 2 H, 7-H, Ar-4-H), 7.34–7.40 (m, 4
H, Ar-2,6-H, Ar-3,5-H) ppm. 13C NMR (100.6 MHz, [D6]acetone): δ =
45.4 (C-1a), 50.1 (C-1), 79.7 (q, JC,F = 30.8 Hz, C-2), 117.2 (C-4), 120.6
(C-6), 125.1 (q, JC,F = 285.3 Hz, CF3), 126.4 (C-5), 126.7 (Ar-C-2,6),
127.0 (C-7), 128.0 (Ar-C-4), 128.9 (Ar-C-3,5), 135.1 (C-8), 135.6 (C-9),
138.5 (Ar-C-1) ppm. 19F NMR (376.5 MHz, CDCl3): δ = –84.2 ppm. IR
Major diastereomer, rel-(1R,1aS,3aS,7aS)-1-Phenyl-2-(trifluoro-
methyl)-1,1a,3a,4,5,6,7,7a-octahydroazireno[1,2-a]quinoxaline
(8a): a pale yellow viscous oil: 1H NMR (600.1 MHz, CDCl3): δ = 1.25–
1.36 (m, 1 H, 4-Hax and 6-Hax), 1.39–1.48 (m, 1 H, 5-Hax), 1.59–1.68
(m, 1 H, 7-Hax), 1.78–1.82 (m, 1 H, 6-Heq), 1.83–1.87 (m, 1 H, 5-Heq),
3
3
3
1.92 (ddd, J7a-H,7-Heq = 4.2, J3a-H,7a-H = 9.2, J7a-H,7-Hax = 11.5 Hz, 1
H, 7a-H), 2.17–2.21 (m, 1 H, 7-Heq), 2.40–2.48 (m, 1 H, 4-Heq), 2.50
3
5
3
(dd, J1-H,1a-H = 3.1, J1a-H,3a-H = 1.3 Hz, 1 H, 1a-H), 2.79 (d, J1-H,1a-
= 3.1 Hz, 1 H, 1-H), 3.19–3.29 (m, 1 H, 3a-H), 7.24–7.39 (m, 5 H,
H
Ph) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 24.8 (C-6), 25.2 (C-5),
33.0 (C-4), 34.04 (C-7), 37.3 (C-1a), 52.7 (C-1), 60.7 (C-3a), 67.1 (C-7a),
(KBr): ν = 1113, 1132, 1151 (C–F), 3161 (N–H), 3407 (O–H) cm–1. MS
1
119.2 (q, JC,F = 277.2 Hz, CF3), 126.1 (Ph-Co), 127.8 (Ph- Cp), 128.5
˜
(EI): m/z (%) = 306 (35) [M]+, 207 (100), 129 (22). HRMS (ESI): calcd.
for C16H13BrF3N2OH+ [M + H]+ 307.1053; found 307.1047.
C16H13F3N2O (306.29): calcd. C 62.74, H 4.28, N 9.15; found C 62.86,
H 4.57, N 8.75.
2
(Ph-Cm), 137.7 (Ph-Ci), 158.9 (q, JC,F = 35.1 Hz, C-2) ppm. 19F NMR
(282.4 MHz, CDCl3): δ = –73.4 ppm.
Minor diastereomer, rel-(1R,1aS,3aR,7aR)-1-Phenyl-2-(trifluoro-
methyl)-1,1a,3a,4,5,6,7,7a-octahydroazireno[1,2-a]quinoxaline
(8b): a pale yellow viscous oil: 1H NMR (600.1 MHz, CDCl3): δ = 1.20–
1.27 (m, 1 H, 7-Hax), 1.32–1.49 (m, 3 H, 4-Hax, 5-Hax, 6-Hax), 1.85–1.91
rel-(1S,1aR,2R)-1-p-Tolyl-2-trifluoromethyl-1,1a,2,3-tetra-
hydroazireno[1,2-a]quinoxalin-2-ol (12b): Pale yellow solid
(233 mg, 73 %), m.p. 145–146 °C. 1H NMR (400.1 MHz, [D6]acetone):
δ = 2.30 (s, 3 H, ArCH3), 2.97 (m, 1 H, 1a-H), 3.49 (m, 1 H, 1-H), 5.90
(br. s, 1 H, NH), 6.49 (s, 1 H, OH), 6.74–6.79 (m, 1 H, 6-H), 6.88–6.92
(m, 1 H, 4-H), 6.96–7.02 (m, 1 H, 5-H), 7.14–7.19 (m, 2 H, Ar-3,5-
H), 7.23–7.27 (m, 3 H, 7-H, Ar-2,6-H) ppm. 13C NMR (100.6 MHz,
3
3
(m, 2 H, 6-Heq, 5-Heq), 2.23 (ddd, J7a-H,7-Heq = 3.4, J3a-H,7a-H = 9.6,
3J7a-H,7-Hax = 11.8 Hz, 1 H, 7a-H), 2.35–2.40 (m, 1 H, 7-Heq), 2.43–2.48
(m, 1 H, 4-Heq), 2.87 (dd, J1-H,1a-H = 3.1, J1a-H,3a-H = 1.3 Hz, 1 H, 1a-
3
5
3
H), 2.91–2.98 (m, 1 H, 3a-H), 3.49 (d, J1-H,1a-H = 2.4 Hz, 1 H, 1-H),
7.27–7.36 (m, 5 H, Ph) ppm. 13C NMR (150.9 MHz, CDCl3): δ = 25.5
[D6]acetone): δ = 20.8 (ArCH3), 45.3 (C-1), 50.0 (C-1a), 79.7 (q, JC,F
=
(C-5), 25.9 (C-6), 31.6 (C-7), 33.62 (C-4), 38.4 (C-1a), 39.0 (C-1), 55.3
30.9 Hz, C-2), 117.1 (C-4), 120.5 (C-6), 125.3 (q, JC,F = 285.1 Hz, CF3),
126.3 (C-5), 126.6 (Ar-C-2,6), 126.9 (C-7), 129.6 (Ar-C-3,5), 135.1 (C-8),
135.4 (Ar-C-1), 135.6 (C-9), 137.6 (Ar-C-4) ppm. 19F NMR (376.5 MHz,
[D6]acetone): δ = –84.1 ppm. 15N NMR (40.6 MHz, [D6]acetone): δ =
–310.1 (N-4), –333.9 (N-1) ppm. MS (EI): m/z (%) = 198 (100), 129
1
(C-7a), 56.4 (C-3a), 119.4 (q, JC,F = 277.9 Hz, CF3), 126.5 (Ph-Co),
2
128.1 (Ph-Cm), 128.6 (Ph-Cp), 137.1 (Ph-Ci), 156.6 (q, JC,F = 34.3 Hz,
C-2) ppm. 19F NMR (282.4 MHz, CDCl3): δ = –73.5 ppm. HRMS (ESI):
calcd. for C16H17F3N2H+ [M + H]+ 295.1417; found 295.1408.
(46). IR (KBr): ν = 1182, 1195, 1221 (C–F), 3326 (O–H) cm–1
C17H15F3N2O (320.31): calcd. C 63.75, H 4.72, N 8.75; found C 63.76,
H 4.75, N 8.54.
.
2-(4-Nitrophenyl)-1-phenyl-1,1a,3a,4,5,6,7,7a-octahydro-
azireno[1,2-a]quinoxaline (9): Brown-yellow crystals, obtained as
a mixture of diastereomers (23:77; 246 mg, 71 %), m.p. 162–164 °C.
˜
Major diastereomer, rel-(1R,1aS,3aS,7aS)-2-(4-Nitrophenyl)-1-
phenyl-1,1a,3a,4,5,6,7,7a-octahydroazireno[1,2-a]quinoxaline
(9a): 1H NMR (400.1 MHz, CDCl3): δ = 1.29–1.56 (m, 3 H, CH2), 1.66–
1.73 (m, 1 H, CH2), 1.80–1.99 (m, 3 H, CH2), 2.19–2.22 (m, 1 H, CH2),
2.47–2.51 (m, 1 H, CH), 2.64 (d, J = 3.1 Hz, 1 H, CH), 2.75 (d, J =
3.1 Hz, 1 H, CH), 3.27–3.34 (m, 1 H, CH), 7.31–7.41 (m, 5 H, Ph), 8.02
(d, J = 8.9 Hz, 2 H, 4-NO2C6H4), 8.20 (d, J = 8.9 Hz, 2 H, 4-NO2C6H4)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 24.8 (CH2), 25.2 (CH2), 33.7
(CH2), 34.1 (CH2), 40.5 (CH), 52.1 (CH), 60.9 (CH), 67.0 (CH), 123.5
(Ar), 125.8 (Ar), 126.9 (Ar), 127.6 (Ar), 128.6 (Ar), 138.4 (Ar), 142.1
(Ar), 148.8 (Ar), 163.2 (C=N) ppm.
rel-(1S,1aR,2R)-1-(4-Chlorophenyl)-2-(trifluoromethyl)-1,1a,2,3-
tetrahydroazireno[1,2-a]quinoxalin-2-ol (12c): Pale yellow solid
(284 mg, 83 %), m.p. 195–197 °C. 1H NMR (600.1 MHz, [D6]DMSO):
3
4
δ = 2.88 (dd, J1-H,1a-H = 3.2, J1a-H,OH = 2.7 Hz, 1 H, 1a-H), 3.47 (d,
4
3J1-H,1a-H = 3.2 Hz, 1 H, 1-H), 6.63 (d, J1a-H,OH = 2.7 Hz, 1 H, OH),
3
3
4
6.69 (ddd, JH,H = 7.7, JH,H = 7.3, JH,H = 1.5 Hz, 1 H, 6-H), 6.90 (dd,
3JH,H = 7.9, 4JH,H = 1.5 Hz, 1 H, 4-H), 6.96 (ddd, 3JH,H = 7.9 Hz, 3JH,H
=
4
3
4
7.3, JH,H = 1.5 Hz, 1 H, 5-H), 7.16 (dd, JH,H = 7.7, JH,H = 1.5 Hz, 1
H, 7-H), 7.32–7.34 (m, 1 H, Ho), 7.39–7.42 (m, 1 H, Hm) ppm. 13C NMR
2
(100.6 MHz, [D6]DMSO): δ = 43.6 (C-1), 49.2 (C-1a), 79.7 (q, JC,F
30.2 Hz, C-2), 116.5 (CH, C-4), 119.2 (CH, C-6), 124.0 (q, JC,F
=
=
287.9 Hz, CF3), 125.7 (CH, C-5), 126.0 (CH, C-7), 127.9 (2 CH, Co),
128.4 (2 CH, Cm), 132.1 (Cp), 133.5 (C-7a), 135.4 (C-3a), 136.8 (Ci)
ppm. 19F NMR (376.5 MHz, [D6]DMSO): δ = –82.5 ppm. HRMS (ESI):
calcd. for C16H12ClF3N2OH+ [M + H]+ 341.0663; found 341.0668.
Minor diastereomer, rel-(1R,1aS,3aR,7aR)-2-(4-Nitrophenyl)-1-
phenyl-1,1a,3a,4,5,6,7,7a-octahydroazireno[1,2-a]quinoxaline
(9b): 1H NMR (400.1 MHz, CDCl3): δ = 2.28–2.39 (m, 2 H, CH2), 2.99–
3.07 (m, 1 H, CH), 3.14 (d, J = 1.8 Hz, 1 H, CH), 3.62 (d, J = 1.8 Hz, 1
H, CH), 7.93 (d, J = 8.9 Hz, 2 H, 4-NO2C6H4) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 25.5 (CH2), 26.0 (CH2), 31.6 (CH2), 34.3 (CH2),
rel-(1S,1aR,2R)-1-(3-Methoxyphenyl)-2-(trifluoromethyl)-
1,1a,2,3-tetrahydroazireno[1,2-a]quinoxalin-2-ol (12d): Pale yel-
Eur. J. Org. Chem. 2016, 1612–1618
www.eurjoc.org
1617
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
low solid (308 mg, 92 %), m.p. 176–177 °C. 1H NMR (400.1 MHz,
[D6]acetone): δ = 3.02 (m, 1 H, CH), 3.53 (m, 1 H, CH), 3.78 (s, 3 H,
MeO), 5.90 (br. s, 1 H, NH), 6.76–6.79 (m, 1 H), 6.84–6.86 (m, 1 H),
Elsevier, Amsterdam, 2008, p. 553–778; k) K. Müller, C. Faeh, F. Diederich,
Science 2007, 317, 1881–1886; l) S. V. Druzhinin, E. S. Balenkova, V. G.
Nenajdenko, Tetrahedron 2007, 63, 7753–7808; m) K. L. Kirk, J. Fluorine
Chem. 2006, 127, 1013–1039; n) G. Theodoridis, Fluorine-Containing
Agrochemicals: An Overview of Recent Developments, in: Advances in Fluo-
rine Science, vol. 2 (Ed.: A. Tressaud), Elsevier, Amsterdam, 2006, p. 121–
175; o) M. Shimizu, T. Hiyama, Angew. Chem. Int. Ed. 2005, 44, 214–231;
Angew. Chem. 2005, 117, 218–234; p) V. G. Nenajdenko, A. V. Sanin, E. S.
Balenkova, Russ. Chem. Rev. 1999, 483–505; q) V. G. Nenajdenko, A. V.
Sanin, E. S. Balenkova, Molecules 1997, 2, 186–232.
3
6.90 (d, JH,H = 7.8 Hz, 1 H), 6.94–7.02 (m, 3 H, Ar), 7.24–7.29 (m, 2
H) ppm. 13C NMR (100.6 MHz, [D6]acetone): δ = 45.7 (CH), 50.3 (CH),
2
55.4 (MeO), 79.9 (q, JC,F = 31.0 Hz, CCF3), 112.3 (CH, Ar), 113.9 (CH,
Ar), 117.4 (CH, Ar), 119.3 (CH, Ar), 120.8 (CH, Ar), 124.9 (q, JC,F
=
285.3 Hz, CF3), 126.7 (CH, Ar), 127.2 (CH, Ar), 130.3 (CH, Ar), 135.1
(Ar), 135.8 (Ar), 140.2 (Ar), 160.8 (Ar) ppm. 19F NMR (376.5 MHz,
CDCl3): δ = –84.5 ppm. HRMS (ESI): calcd. for C17H15F3N2O2H+ [M +
H]+ 337.1158; found 337.1151.
[5] a) For reviews, see: A. Yu. Rulev, Russ. Chem. Rev. 1998, 67, 279–293; b)
A. Yu. Rulev, Russ. Chem. Rev. 2011, 80, 197–218; c) L. Degennaro, P.
Trinchera, R. Luisi, Chem. Rev. 2014, 114, 7881–7929. For recent examples,
see: d) A. Yu. Rulev, S. Azad, H. Kotsuki, J. Maddaluno, Eur. J. Org. Chem.
2010, 6423–6429; e) M. Görmen, R. Le Goff, A. M. Lawson, A. Daïch, S.
Comesse, Tetrahedron Lett. 2013, 54, 2174–2176; f) Z. Amara, E. Drge, C.
Troufflard, P. Retailleau, M.-E. Tran Huu-Dau, D. Joseph, Chem. Eur. J.
2014, 20, 15840–15848.
[6] a) A. Yu. Rulev, V. M. Muzalevskiy, E. V. Kondrashov, I. A. Ushakov, A. R.
Romanov, V. N. Khrustalev, V. G. Nenajdenko, Org. Lett. 2013, 15, 2726–
2729; b) V. M. Muzalevskiy, Yu. A. Ustynyuk, I. P. Gloriosov, V. A. Chertkov,
A. Yu. Rulev, E. V. Kondrashov, I. A. Ushakov, A. R. Romanov, V. G. Nenaj-
denko, Chem. Eur. J. 2015, 21, 16982–16989.
[7] a) A. Yu. Rulev, I. A. Ushakov, V. G. Nenajdenko, E. S. Balenkova, M. G.
Voronkov, Eur. J. Org. Chem. 2007, 6039–6045; b) A. Yu. Rulev, I. A. Us-
hakov, V. G. Nenajdenko, Tetrahedron 2008, 64, 8073–8077.
[8] a) V. M. Muzalevskiy, V. G. Nenajdenko, A. Yu. Rulev, I. A. Ushakov, G. V.
Romanenko, A. V. Shastin, E. S. Balenkova, G. Haufe, Tetrahedron 2009,
65, 6991–7000; b) 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; c) V. G. Nenajdenko, V. M. Muzalevskiy, A. V.
Shastin, E. S. Balenkova, E. V. Kondrashov, I. A. Ushakov, A. Yu. Rulev, J.
Org. Chem. 2010, 75, 5679–5688; d) A. Yu. Rulev, I. A. Ushakov, E. V.
Kondrashov, V. M. Muzalevskiy, A. V. Shastin, V. G. Nenajdenko, J. Fluorine
Chem. 2011, 132, 945–950.
Acknowledgments
This work was supported by the Russian Foundation for Basic
Research (RFBR) (grant number 13-03-00063-a; synthesis of
compounds 6a, 6b, 12a, and 12b), and the Russian Science
Foundation (grant number 14-13-00083, synthesis of starting
enones 1, compounds 6c–6f, 7–11, 12c, and 12d; structural
elucidations of 8a, 8b, and 12c). Some spectral and analytical
data were obtained using the equipment of the Baykal analyti-
cal center for collective use SB RAS, which is also acknowl-
edged. The authors acknowledge partial support in measuring
NMR spectroscopic data from M. V. Lomonosov, Moscow State
University Program of Development.
Keywords: Fluorine · Nitrogen heterocycles · Small ring
systems · Ketones · Cyclization · Reaction mechanisms
[9] S. Roy, M. P. Davydova, R. Pal, K. Gilmore, G. A. Tolstikov, S. F. Vasilevsky,
[1] a) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257–
10274; b) A slightly lower number (51 drugs) was found in: R. D. Taylor,
M. MacCoss, A. D. G. Lawson, J. Med. Chem. 2014, 57, 5845–5859.
[2] a) The poster containing structural formulas of the top 200 selling drugs
can be downloaded from: http://cbc.arizona.edu/njardarson/group; b)
N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem. Educ. 2010, 87,
1348–1349.
I. V. Alabugin, J. Org. Chem. 2011, 76, 7482–7490.
[10] E. Pretsch, P. Bühlmann, M. Badertscher, Structure Determination of Or-
ganic Compounds, Springer-Verlag, Berlin/Heidelberg, Germany, 2009, p.
433.
[11] A. I. Zbruyev, V. V. Vashchenko, A. A. Andryushchenko, S. M. Desenko,
V. I. Musatov, I. V. Knyazeva, V. A. Chebanov, Tetrahedron 2007, 63, 4297–
4303.
[3] For recent reviews, see: a) Fluorine Chemistry, Chem. Rev. 2015, 115, 563–
1306; b) V. G. Nenajdenko (Ed.), Fluorine in Heterocyclic Chemistry,
Springer, Cham, 2014, vol. 1, p. 681, vol. 2, p. 760; c) V. A. Petrov (Ed.),
Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applica-
tions, Wiley, New Jersey, 2009, p. 515; d) A. A. Gakh, K. L. Kirk (Eds.),
Fluorinated Heterocycles, ACS Symposium Series, Oxford University Press/
American Chemical Society, Washington, DC, 2009, p. 360.
[4] For reviews, see: a) E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med. Chem.
2014, 57, 2832–2842; b) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly,
N. A. Meanwell, J. Med. Chem. 2015, 58, 8315–8359; c) D. O'Hagan, J.
Fluorine Chem. 2010, 131, 1071–1081; d) P. V. Ramachandran, Future Med.
Chem. 2009, 1, 771–772; e) R. Filler, R. Saha, Future Med. Chem. 2009, 1,
771–791; f) I. Ojima (Ed.), Fluorine in Medicinal Chemistry and Chemical
Biology, John Wiley & Sons, Chichester, UK, UK, 2009, p. 640; g) S. Purser,
P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320–
330; h) W. L. Hagmann, J. Med. Chem. 2008, 51, 4359–4369; i) J. P. Bégué,
D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, John
Wiley & Sons, Hoboken, 2008; j) A. Tressaud, G. Haufe (Eds.), Fluorine
and Health. Molecular Imaging, Biomedical Materials and Pharmaceuticals,
[12] A. Padwa, L. Gehrlein, R. B. Kinnel, J. Org. Chem. 1975, 40, 1683–1688.
[13] a) A. V. Samoshin, I. S. Veselov, V. A. Chertkov, A. A. Yaroslavov, G. V.
Grishina, N. M. Samoshina, V. V. Samoshin, Tetrahedron Lett. 2013, 54,
5600–5604; b) Y. Zheng, X. Liu, N. M. Samoshina, V. A. Chertkov, A. Franz,
X. Guo, V. V. Samoshin, Natural Product Commun. 2012, 7, 353–358.
[14] V. A. Chertkov, N. M. Sergeyev, J. Am. Chem. Soc. 1977, 99, 6750–6752.
[15] V. A. Chertkov, A. K. Shestakova, D. V. Davydov, Chem. Heterocycl. Compd.
2011, 47, 45–54.
[16] A. V. Fokin, A. F. Kolomiets, N. V. Vasil'ev, Russ. Chem. Rev. 1984, 53, 238–
255.
[17] A. Yu. Rulev, N. Yenil, A. Pesquet, H. Oulyadi, J. Maddaluno, Tetrahedron
2006, 62, 5411–5416.
[18] A. Yu. Rulev, J. Maddaluno, J. Phys. Org. Chem. 2002, 15, 590–598.
[19] H. W. Heine, R. P. Henzel, J. Org. Chem. 1969, 34, 171–175.
[20] V. D. Orlov, Z. Kaluski, N. P. Borob'eva, E. Figas, A. A. Tishchenko, F. G.
Yaremko, Chem. Heterocycl. Compd. 1994, 30, 964–971.
Received: December 18, 2015
Published Online: February 18, 2016
Eur. J. Org. Chem. 2016, 1612–1618
www.eurjoc.org
1618
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim