A general synthesis of bis(o-azaheteroaryl)methane derivatives from N-oxides of azines and azoles

Article abstract of DOI:10.1002/ejoc.201500072

A general method of preparation of derivatives of bis(o-azaheteroaryl)methanes from aromatic N-oxides is reported, the key step of which is a 1,3-dipolar cycloaddition between N-oxides of azines or azoles and in situ generated terminal difluoroalkenes containing an o-azaheteroaryl substituent at the double bond. Selected products were applied for the preparation of two novel unsymmetrical analogues of BODIPY fluorescent dyes, containing both an imidazole and a quinoline or isoquinoline unit.

Full text of DOI:10.1002/ejoc.201500072

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500072
A General Synthesis of Bis(o-azaheteroaryl)methane Derivatives from
N-Oxides of Azines and Azoles
Magdalena Szpunar[a] and Rafał Loska*[a]
Keywords: Synthetic methods / Cycloaddition / Nitrogen heterocycles / Fluorine / Tautomerism
A general method of preparation of derivatives of bis(o-aza-
heteroaryl)methanes from aromatic N-oxides is reported, the
key step of which is a 1,3-dipolar cycloaddition between N-
oxides of azines or azoles and in situ generated terminal di-
fluoroalkenes containing an o-azaheteroaryl substituent at
the double bond. Selected products were applied for the
preparation of two novel unsymmetrical analogues of
BODIPY fluorescent dyes, containing both an imidazole and
a quinoline or isoquinoline unit.
methylpyridines.[12] More recently, this method has been
employed by Kubota and co-workers in their synthesis of a
new class of BODIPY analogues, which were reported to
possess promising optical properties such as larger Stokes
shift and enhanced fluorescence in the solid state.[13] Such
analogues based on unsymmetrical ligands,[14] and particu-
larly those, which contain pyridine units,[15] form a new im-
portant trend in research on fluorescent dyes.
Recently, our group has been involved in developing new
methods of functionalization of the heteroaromatic ring in
positions occupied by hydrogen atoms,[16] in particular
those, which are based on dipolar cycloaddition of aromatic
N-oxides to terminal difluoroalkenes.[17] Further transfor-
mations of the initial difluoroisoxazolidine cycloadduct re-
Introduction
Bis(o-azaheteroaryl)methanes in which the central meth-
ylene or methine carbon atom is connected to heterocyclic
rings containing nitrogen atoms with free electron pairs, i.e.
azine and/or azole (imidazole, pyrazole etc.) units, have
found applications in diverse areas of organic chemistry.
Both symmetrical[1] and unsymmetrical[2] compounds of
this type have been used as ligands in coordination chemis-
try, including transition metal catalysis,[3] as compounds
possessing interesting photophysical properties,[4] or as new
lead structures in medicinal chemistry.[5] They have also
been used in studies on unusual organic molecules such as
tricationic superelectrophiles[6] or bent acyclic allenes.[7]
Some of them have been identified as natural products, for
example arsindoline and similar alkaloids containing a
quinolinylbis(indolyl)methane motif.[8] Usually, compounds
of this type are synthesized by condensation reactions of
bifunctional methylene compounds,[2d,9] for example
malonates with 1,2-phenylenediamines in the synthesis of
bis(2-benzoimidazolyl) or bis(thiazolyl)methenes for bio-
logical studies,[5] or by nucleophilic addition of
lithiated heterocycles to heteroarenecarbaldehydes and
ketones.[2a,2b,2e,10] Some transition-metal-catalyzed pro-
cesses have been developed specifically for the synthesis of
bis(aryl)methanes, but they are suitable mainly for the prep-
aration of compounds containing at least one homoaro-
matic ring.[11] Bis(pyridyl)methanes containing differently
substituted pyridine rings have been obtained by SNAr reac-
tion between 2-halopyridines and carbanions of 2-cyano-
[a] Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01-224 Warsaw, Poland
E-mail: rafal.loska@icho.edu.pl
http://www.icho.edu.pl/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500072.
Scheme 1. Cycloaddition of N-oxides and terminal difluoroalkenes.
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M. Szpunar, R. Loska
SHORT COMMUNICATION
store aromaticity of the original heterocyclic ring and pro-
vide heteroaromatic systems with new aliphatic substituents
in C-2 position of the ring (Scheme 1, top). Applying this
general scheme to dilfuoroalkenes containing a heteroaryl
substituent at the double bond, we have now developed a
method of preparation of unsymmetrical bis(o-azahet-
eroaryl)methane derivatives 3 that gives access to diverse
structures containing different five- and six-membered het-
erocyclic rings (Scheme 1, bottom). Our approach combines
two different aromatic N-oxides and simple, commercially
available fluorinated synthons into bis(heteroaryl)acetic
acid derivatives in two consecutive dipolar cycloaddition
steps, both of which proceed under mild, neutral and transi-
tion-metal-free conditions. We also report our initial
attempts of transforming the obtained quinolinyl(imidazo-
lyl)methanes into their BF2 complexes. As far as we know,
apart from one patent claim,[18] such BODIPY analogues
have not yet been described in the literature.
Scheme 2. Preparation of difluorovinylquinoline 2a and its reaction
with imidazole N-oxide 1b and MeOH.
Difficulties in preparation and purification of alkene 2a
and its limited stability led us to modify our approach to
the synthesis of bis(heteroaryl)methanes. Reactions of
N-oxides 1c–g with PFP and methanol [Scheme 3,
method (A)] or, more efficiently, with methyl perfluoro-
methacrylate [generated in situ from (CF3)2CHCO2Me and
NEt3; Scheme 3, method (B)] provided esters 4, which
readily underwent elimination of HF by tertiary amines
(NEt3, DIPEA). The respective alkenes turned out to be
too electrophilic and water-sensitive to be isolated, but they
could be generated from 4 in the presence of N-oxides to
give the desired bis(heteroaryl)acetic acid esters 3 in a one-
pot process. In an extensive optimization study of the reac-
tion between imidazole N-oxide 1b and 4-methylquinolin-
2-yl-substituted ester 4c the yield of 3b did not exceed 50%.
The best results were obtained by using moderately polar
solvents like THF, AcOEt or PhCF3, 2 equiv. of NEt3 and
performing the reaction at 50 °C for 48 h. Toluene required
a much longer time, and the use of DMF or DCM led to
increased amounts of decomposition products. Utilization
of DIPEA or 1,5-diazabicyclo[4.3.0]non-5-ene instead of
NEt3 did not improve the yield. The yields dropped about
twofold unless the reactions were performed by using
Schlenk techniques and dry solvents. The experiments were
conducted with 0.5 mmol of 4c and 0.75 mmol of 1b. Inter-
estingly, on a 7 mmol scale, 3b was obtained in a much
higher yield of 70%.
Results and Discussion
In principle, heteroaryl-substituted difluoroalkenes 2
could be obtained from 2-acylazines or azoles by a Wittig-
or Julia-type difluoromethylation.[19] Unfortunately, reac-
tions of 2-formyl- or 2-acetylpyridine with CF2Br2/Zn or
ClCF2CO2Na in the presence of phosphines failed due to
the instability of substrates and/or products under the reac-
tion conditions. Some compounds of type 2 are also avail-
able from Pd-catalyzed cross coupling reactions of (di-
fluorovinyl)metal reagents.[20] However, preparation of alk-
enes 2 from readily available N-oxides[21] would avoid the
necessity of preparing halogenated or acylated azine precur-
sors. As reported previously by us[22] and others,[23] cycload-
dition of aromatic N-oxides to simple perfluroalkenes in the
presence of O-, S-, or N-nucleophiles proceeds according to
Scheme 1. In particular, reaction with 2H-pentafluoroprop-
ene (PFP) in the presence of MeOH should provide azines
4 with a CH(CF3)CO2Me substituent, and reaction in the
presence of water, after decarboxylation, would give prod-
ucts 5 with a 2,2,2-trifluoroethyl substituent. Both 4 and 5
after elimination of HF could be the source of 2-heteroaryl-
1,1-difluoroalkenes.
First, we prepared 2-(difluorovinyl)quinoline 2a from 2-
(2Ј,2Ј,2Ј-trifluoroethyl)quinoline 5a, readily obtained from
PFP and quinoline N-oxide 1a (Scheme 2). Attempts to
eliminate HF from 5a by using tertiary amines or DBU,
with or without BF3·OEt2,[24] failed, but 2a could be ob-
tained by using LiHMDS after optimization of solvent and
temperature in only 56% yield, due to its limited stability.
Gratifyingly, reaction of 2a with 1-benzyl-4,5-dimethylimid-
azole 3-oxide 1b and MeOH in THF at room temperature
gave the expected bis(heteroaryl)acetic acid methyl ester 3a
in 40% yield (exclusively in the tautomeric form shown in
Scheme 2 as judged by NMR spectroscopy). However, due
to instability of 3a it could not be fully characterized.
Scheme 3. Preparation of 3,3,3-trifluoropropionic acid methyl
esters 4 from N-oxides and fluoroalkenes. [a] With 16% of 5-
CO2Me regioisomer.
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Bis(o-azaheteroaryl)methane Derivatives from N-Oxides of Azines and Azoles
Examples of preparation of bis(o-azaheteroaryl)acetic correlation spectra. The reaction of thiazole N-oxide was
acid methyl esters 3 (Table 1) demonstrate that it is possible performed at room temperature because of its instability.
to obtain products containing various combinations of het- Unlike the reactions of five-membered N-oxides, the best
erocyclic systems: quinoline, isoquinoline, pyridine, imid- yield of compound 3c containing two quinoline units was
azole and thiazole. Although the yields are moderate, it obtained in polar solvents at room temperature: 71% in
should be noted that products 3 are formed in a multistep DMF and 62% in MeCN.
process, which includes elimination of HF from 4, cycload-
Compounds 3, that contain quinoline or pyridine rings,
dition, cleavage of the isoxazolidine cycloadduct, hydrolysis exist in solution as mixtures of C–H and N–H tautomers,
of acyl fluoride and finally decarboxylation. Unlike 3a, all or even exclusively as N–H tautomers in which the six-
products in Table 1 were stable and suitable for standard membered heterocyclic ring is not aromatic and contains
spectroscopic characterization; the structures of representa- an exocyclic double bond. The ratios of the two tautomers
tive examples has been additionally confirmed by 2D NMR generally reflect the resonance stabilization of different het-
eroaromatic systems present in bis(heteroaryl)acetic esters
3. Compounds 3 existing fully or partially as N–H tauto-
mers are characterized by the presence of absorption bands
Table 1. Synthesis of bis(o-azaheteroaryl)acetic esters 3.
in the visible region of their UV/Vis spectra and characteris-
tic NMR signals of the bridging carbon atom (δ ≈ 80 ppm)
and N–H proton (δ ≈ 13 ppm). On the other hand, due to
the presence of an sp3 carbon atom between the heteroaro-
matic rings, C–H tautomers exhibit diasterotopism of pro-
tons in the methylene groups of Bn and nPr substituents.
Moderate yields of products 3 result in part from side
reactions leading to deoxygenated azines and imidazoles.
Their formation could be explained by a non-concerted
character of cycloaddition between 1 and highly electro-
philic alkene 2 and side reactions that follow the initial nu-
cleophilic attack of the N-oxide oxygen on the terminal CF2
group of 2. Formation of deoxygenated imidazoles has been
similarly explained in the case of reactions of their N-oxides
with thioketenes.[25]
Esters 3 can be readily transformed into the correspond-
ing methylene derivatives by basic hydrolysis and subse-
quent spontaneous decarboxylation (Scheme 4). These
products do not show tautomerism analogous to 3, which
suggests that partially nonaromatic N–H tautomers of 3 are
stabilized by the electron-withdrawing effect of the ester
group and formation of the extended π-electron system, and
possibly also by the intramolecular hydrogen bond.
Scheme 4. Hydrolysis and decarboxylation of 3.
In the presence of BF3·OEt2 and NEt3 in DCM bis(het-
eroaryl)methanes 6b and 6i gave complexes 7b and 7i in
25% and 37% yield, respectively, which are novel unsym-
metrical analogues of fluorescent BODIPY dyes (Figure 1);
7b,i are fluorescent in solution, but their limited stability
precluded a systematic study of photophysical properties.
Similar reactions of the parent esters 3 with BF3·OEt2 are
potentially less useful as they give mixtures of 7 and analo-
gous complexes substituted with an ester group in the meso
position, together with unidentified side products.
[a] Ratio of C–H/N–H tautomers. Each compound is shown in its
predominating form. [b] DMF, room temp., 20 h. [c] 1 equiv. of
NEt3. [d] THF, 1 equiv. of NEt3. [e] Toluene, r.t., 24 h.
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M. Szpunar, R. Loska
SHORT COMMUNICATION
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Acknowledgments
This work was supported by the National Science Centre (grant
UMO-2011/03/D/ST5/06066).
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Received: January 16, 2015
Published Online: February 23, 2015
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