2
M.V. Varaksin et al. / Journal of Organometallic Chemistry xxx (2018) 1e6
electron withdrawing effect of fluorine groups in the aromatic ring.
In this study, an elucidation of the reactivity of pentafluorophenyl
lithium in transition metal-free C-C couplings with azines and their
activated forms, N-oxides, has been carried out for the first time. It
should be noted that no direct C-Li/C-H coupling reactions of
pentafluorophenyllithium with heteroarenes have so far been
described. As a result of these stage- and atom-economic C(sp2)-H
functionalizations of azines, a wide variety of novel bifunctional
organic molecules, bearing both polyfluoroaryl and heterocyclic
scaffolds, have successfully been obtained.
stretching band at n
3066 cmꢀ1. The mass spectra of all compounds
measured exhibit the corresponding molecular ion peaks. In the 1H
NMR spectra of fluorinated heterocyclic compounds 4, 5, 8, and 9,
the resonance signals of (hetero)aryl substituents are observed at
d
7.35e8.51 ppm, while in the 13C NMR spectra of the same com-
pounds
d
the
corresponding
signals
are
exhibited
at
122.7e160.8 ppm. In the 19F NMR spectra, the fluorine nuclei
resonate as three detached multiplet signals at
d
ꢀ162.3 e (ꢀ134.4)
ppm. For instance, the 1H NMR spectra of pentafluoro-containing
dihydrotriazine 4 (a), triazine 5 (b), and triazine-N-oxide 9 (c) are
According to the modern concept, the nucleophilic substitution
of hydrogen (SHN) [7] is a two-step process that can be implemented
in two ways, either either “Addition - Oxidation” SHN(AO) or the
“Addition - Elimination” SHN(AE) protocols (Table 1). In case of C-H
functionalization of 1,2,4-triazines, the stable pentafluorophenyl
presented in Fig. 1. Notably, in the 1H NMR spectra of the H-adduct
s
4, the signal of proton attached to the sp3-hybridized carbon
C(sp3)eH is observed at
6.41 ppm, while the NH proton resonates
at
11.48 ppm. In the 13C NMR spectra of dihydro triazine 4, the
carbon resonance C(sp3)eH signal is observed at
46.4 ppm; no
d
d
d
substituted dihydrotriazine 4 is formed as the intermediate sH
-
signals in these fields have been found in the spectra of hetero-
aromatic analogue 5.
adduct at the first stage in 63% yield. In order to convert 4 into the
corresponding SHN product, a number of oxidants, such as DDQ, o-
Chloranil, and p-Chloranyl, have been tested to find out the optimal
reaction conditions. It has finally been found that the best yield of
the target product (63%) can be achieved using DDQ.
The structures of polyfluroaryl-substituted heterocycles have
also been proved by X-ray analysis (Fig. 2). The appropriate crystals
of 8c were obtained by crystallization from a mixture of heptane/
CH2Cl2, 1:1. In accordance with the X-ray analysis data, the mono
crystals of 8c proved to belong to the space group P121/n1
(monoclinic crystal system). No considerable deviations in bond
lengths and bond angles from the standard values [12] have been
observed. Pentafluorobenxene and phthalazine rings are nearly
planar, and deflections of atoms from the mean square plane are
less than 0.021 Å. The angle between the median planes of the
pentafluorobenzene and phthalazine rings is 78.09ꢁ.
In case of C-H modifications of mono-, di-, and triazine-N-ox-
ides, lithium compound 2 is added to the C¼NþeO- bond of azine
N-oxides to afford unstable N-hydroxy s
H-adducts 7a-d at the first
stage. Intermediates 7a-d can then be converted into a variety of
products 5, 8a-c and 9, depending on azaaromatic structures and
reaction conditions used for the second step (aromatization). Thus,
pentafluorophenyl azines 5, 8a-c have been found to be formed in
54e78% yields through the eliminative aromatization. Studying the
reactivity of triazines, the C-C coupling conditions have also been
optimized by using various deoxygenating agents such as AcCl,
Ac2O, and TFFA. The highest yield of triazine 5 (65%) was shown
when the reaction mixture had been treated with AcCl as a deox-
ygenating reagent. Additionally, in order to obtain the C-C coupling
products of azine-N-oxides with retention of N-oxide function, the
features of oxidative aromatization have been studied as well. It has
been found that pentafluorophenyl azine 9 is the only product of
the reaction of 3,6-diphenyl-1,2,4-triazine-4-oxide 6d. The use of
mono- and diazine-N-oxides in the deoxygenative coupling with
pentafluorobenzene lithium 2 has been observed to give no desired
biheterocyclic products, the reaction mass being a mixture of
starting materials and degradation products.
3. Conclusion
In summary, a pot, atom and step economic (PASE) method has
been developed, based on exploiting the green chemistry-oriented
SHN methodology. A number of biheterocyclic compounds, bearing
both pentafluorophenyl and azaaromatic fragments, linked to each
other through the C-C bonds, have been obtained in good to
excellent yields. The SHN approach used enables the fluorinated
bi(hetero)arene ensembles to be obtained from penta-
fluorobenzene and azines in situ. The compounds synthesized seem
to be of interest in drug and agrochemical design, as well as they
can possibly be used in molecular electronic devices and other
advanced materials.
Pentafluorophenyl-modified azaheterocycles obtained contain
both the novel compounds 4, 5, 8c, 9 and the known ones 8a and
8b. It should be noted that the described pentafluorophenyl-
containing quinoline 8a and quinoxaline 8b have earlier been ob-
tained from chloroazines or/and azinyl tosylate by using Pd(II)- or
Cu(I)-catalyzed C-C coupling reactions. Contrary to that, the SNH
approach used at the present work is based on nucleophilic attack
of pentafluorophenyl lithium (generated in situ) on the azine
C(sp2)-H bond. It enables one to carry out analogous C-C coupling
reactions in full accordance with the principles of pot and stage
efficiency. In other words, the use of SHN reactions provides com-
parable yields of the desired products without a prior incorporation
of chlorine (or other auxiliary groups) into azine and catalysis by
transition metals, such as palladium and copper (Table 1, Entries 4
and 5).
4. Experimental section
4.1. General experimental methods
The 1H NMR (400 MHz) and 13C NMR (100 MHz), 19F (376 MHz)
spectra were recorded using TMS as the internal standard and
DMSO-d6 as a deuterated solvent. The X-ray diffraction analysis was
performed on a diffractometer, equipped with CDD detector (Mo
KR graphite-monochromated radiation,
l
¼ 1.54184 Å,
u-scanning
technique, the scanning step was 1ꢁ and the exposure time per
frame was 10 s at 295(2) K. Analytical absorption correction was
used in the reflection intensity integration [13]. The structure was
solved by the direct method and refined applying full matrix least-
squares versus F2 with anisotropic displacement parameters for
hkl
The compounds obtained have been characterized by elemental
analysis, IR, 1H, 13C, 19F NMR, as well as the data of mass spec-
trometry. The IR, 1H, 13C, and 19F NMR spectra have been found to be
in a full compliance with the proposed structures. In particular, the
characteristic absorption bands, corresponding to the stretching
all non-hydrogen atoms using the SHELX97 program package [14].
All hydrogen atoms were located in different electron density maps
and refined using a riding model with fixed thermal parameters.
The mass spectra were recorded on a mass spectrometer with
sample ionization by electron impact (EI). The IR spectra were
recorded using a Fourier-transforminfrared spectrometer equipped
with a diffuse reflection attachment. The elemental analysis was
carried out on a CHNS/O analyzer. The course of the reactions was
vibrations of C¼N groups, have been registered at
n 1596-
1655 cmꢀ1 in the IR spectra for compounds 4, 5, 8, 9. The IR spec-
trum of dihydro compound 4 contains also the characteristic NH
j.jorganchem.2018.01.020
Varaksin, Mikhail V.
