Regioselective annulation of nitrosopyridine with alkynes: Straightforward synthesis of N-oxide-imidazopyridines

Article abstract of DOI:10.1039/c5cc00533g

We have developed a novel method for the regioselective annulation of 2-nitrosopyridines with variably substituted alkynes under mild reaction conditions. This approach allows the annulation of alkynes with 2-nitrosopyridines under reagent- and catalyst-free reaction conditions. The developed method shows excellent functional group tolerance and provides easy access to N-oxide-imidazo[1,2-a]pyridines.

Full text of DOI:10.1039/c5cc00533g

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Regioselective annulation of nitrosopyridine
with alkynes: straightforward synthesis of
Cite this:DOI: 10.1039/c5cc00533g
N-oxide-imidazopyridines†
Received 19th January 2015,
Accepted 24th February 2015
Srimanta Manna,ab Rishikesh Narayan,a Christopher Golz,c Carsten Strohmannc and
Andrey P. Antonchick*ab
DOI: 10.1039/c5cc00533g
www.rsc.org/chemcomm
We have developed a novel method for the regioselective annulation of well.7 The [2+2] cycloaddition was successfully applied in the
2-nitrosopyridines with variably substituted alkynes under mild reaction synthesis of carbazole derivatives by reactions of nitrosoarenes
conditions. This approach allows the annulation of alkynes with with in situ generated arynes.8 Nicholas’ group developed a
2-nitrosopyridines under reagent- and catalyst-free reaction conditions. synthesis of indole derivatives based on the thermal annulation
The developed method shows excellent functional group tolerance and of nitrosoarenes with excess of alkynes by stepwise diradical
provides easy access to N-oxide-imidazo[1,2-a]pyridines.
cycloaddition.9 Recently, nitrosoarenes were used in the [3+2]
cycloaddition reaction of allylstannanes and donor–acceptor
Heterocyclic compounds constitute the majority of organic cyclopropanes by Studer and co-workers.10 Herein, we report the
compounds. Nitrogen-containing heterocycles are present in many first intermolecular annulation of 2-nitrosopyridine derivatives with
natural compounds, biological probes, chemicals and materials.1 substituted alkynes for the regioselective access of N-oxide-imidazo-
However, the chemical space which can be occupied by relatively [1,2-a]pyridines under operationally simple, mild and metal-free
simple bicyclic heteroaromatic compounds has not been fully reaction conditions. Furthermore, deoxygenation of the obtained
explored and hundreds of novel molecules still remain to be products for the synthesis of imidazo[1,2-a]pyridines and annulation
synthesized.2 A considerable amount of novel ring systems success- of alkenes under metal-free conditions is demonstrated.
fully enter the drug space annually.3 Therefore, the development of
novel efficient methods of heterocycle synthesis is highly desired of heterocycles under mild transition-metal free conditions,11,12
and represents a field of intense investigation. we were interested in the metal-free synthesis of N-oxide-imidazo-
In line with our research on the synthesis and functionalization
Cycloaddition and annulation reactions are representing a [1,2-a]pyridines through direct annulation of 2-aminopyridine deri-
powerful practical method for the synthesis of heterocyclic products. vatives with alkynes.13–15 The N-oxide group in these products can
This elegance is mainly derived from the atom-economical be reduced to provide the parent imidazo[1,2-a]pyridine scaffold.
nature of this reaction and the possibility of formation of several Furthermore, N-oxide-imidazo[1,2-a]pyridines are synthetically
bonds in a single operation.4 The strategy based on cycloaddition of challenging heteroaromatic compounds, because they cannot be
nitrosoarenes has emerged as a new route to construct heterocycles obtained by oxidation of the corresponding imidazopyridines and
where nitrosoarenes were used only as a 2p-component.5 The groups direct routes for their synthesis remain unexplored.16
of Yamamoto and Studer used 2-nitrosopyridine as dienophile
Initially, the reaction of 2-nitrosopyridine (1a) with diphenyl-
for enantioselective Cu(I) catalyzed nitroso-Diels–Alder reaction.6 acetylene (2a) was chosen as model reaction (Scheme 1). After
Copper-catalyzed enantioselective [2+2] cycloaddition of nitroso- optimization of reaction conditions, we were delighted to obtain
pyridine with ketenes was established in the Studer group as the desired product 3a with 86% yield in 12 h using HFIP
(1,1,1,3,3,3-hexafluoro-2-propanol) as solvent in the absence of
any reagent, catalyst or additive (Scheme 1; see ESI† for details).
a Max-Planck Institute of Molecular Physiology, Abteilung Chemische Biologie,
Otto-Hahn Strasse 11, 44227, Dortmund, Germany.
E-mail: Andrey.Antonchick@mpi-dortmund.mpg.de
b
¨
¨ ¨
Technische Universitat Dortmund, Fakultat fur Chemie und Chemische Biologie,
Chemische Biologie, Otto-Hahn Strasse 6, 44227, Dortmund
c
¨
¨ ¨
Technische Universitat Dortmund, Fakultat fur Chemie und Chemische Biologie,
Anorganische Chemie, Otto-Hahn Strasse 6, 44227, Dortmund
† Electronic supplementary information (ESI) available. CCDC 1018375. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c5cc00533g
Scheme 1 Annulation of 2-nitrosopyridine with alkyne.
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With a set of optimized reaction conditions in hand, we obtained products were supported by X-ray crystallographic
concentrated on investigating the scope of annulation. At first, analysis of product 3h.17 Afterwards, various symmetrical bis-aryl
2-nitrosopyridine derivatives were tested in the annulation with alkynes were tested in the annulation (compounds 3i–3n). The
diphenylacetylene (Scheme 2). To our delight, a range of substituted alkynes bearing electron-rich as well as electron-withdrawing
2-nitrosopyridines showed efficient reactivity (products 3b–3h). groups on the aryl part reacted well to provide the corresponding
2-Nitrosopyridines substituted with electron-donating and strong annulation products 3i–3m in excellent yields (77–95%). However,
electron-withdrawing substituents such as nitro and trifluoromethyl the reaction of electron poor derivatives required higher tempera-
were well tolerated under the developed mild reaction conditions tures (products 3l and 3m). Notably, 1,2-di(thiophen-2-yl)ethyne
providing the desired products in 64–95% yield. Moreover, the reacted smoothly to provide 3n with a yield of 92%.
efficiency of the reaction remained high, irrespective of the position
After exploring the scope of symmetrical alkynes we switched
of the substituents on the pyridine ring. The structures of the our attention to unsymmetrical derivatives. First, the reactivity of
the terminal alkynes was tested (products 3o–3s). All the terminal
alkynes with aryl substituents were found to react efficiently
irrespective of the electronic nature of the substituents present
on the aryl ring. In all cases the corresponding products could be
obtained in good to excellent yields. Furthermore, the annulation
proceeds with shorter reaction times and at a lower temperature in
comparison to disubstituted alkynes. The regioselectivity was found
to be absolute with electron rich aryl groups such as 6-methoxy-2-
naphthyl and 3,4-dimethoxyphenyl (compounds 3o and 3p).
The selectivity was found to be good in the case of 4-fluorophenyl
with a ratio of 4 : 1 (compound 3r), too. However, in the case of
4-cyanophenyl and phenyl groups, the regioselectivity was reduced
(compounds 3s and 3q). In all examples of terminal alkynes, the
major product carried the aryl ring at the C3 position of N-oxide
imidazo[1,2-a]pyridines 3. Monoalkyl acetylenes were also tried, but
unfortunately failed to react under these reaction conditions. It is
notable that the regioselectivity of alkyne addition is opposite to
gold-catalyzed processes and complementary to them.14 Later, we
evaluated the scope of unsymmetrically disubstituted alkynes. At
first, we tried alkyl-arylsubstituted unsymmetrical alkynes (com-
pounds 3t–3w). Pleasingly, all of them reacted efficiently to furnish
the corresponding annulation products in good to excellent yields
with complete regioselectivity. Notably, an alkyne bearing an
unprotected hydroxy group in the side chain also reacted well to
provide product 3u in moderate yield. Then we moved to bis-aryl
substituted unsymmetrical alkynes, which display similar reactivity
like alkyl–aryl alkynes. These alkynes were also found to react very
efficiently with high yields and exclusive regioselectivity (com-
pounds 3x–3z). The relatively electron-poor of the two aryl groups
was found to occupy the C2 position, whereas the electron-rich one
went to the C3 position of N-oxide imidazo[1,2-a]pyridines 3. The
regioselectivity of the reactions with unsymmetrical alkynes was
determined through NOE experiments (see ESI† for details).
In a notable example a steroid-derived structurally complex
alkyne was reacted with 2-nitrosopyridine to provide the corres-
ponding annulated product in an excellent yield of 85% as a single
stereoisomer (3aa). This example clearly demonstrates the utility of
this novel reaction even in complex molecular settings and its
functional group tolerance. Finally, in an interesting example where
conjugated bis-alkyne (1,4-diphenylbuta-1,3-diyne) was used as
a coupling partner, a mixture of bis- and mono-annulation was
Scheme 2 Scope of annulation with alkynes: nitrosopyridine (0.25 mmol),
obtained in an appreciable ratio of 8 : 1.18 Formation of a single
alkyne (0.28 mmol) in HFIP at 40 1C for 12 h. a The reactions were
symmetrical regioisomer of the bis-adduct out of 4 possible
regioisomers by creation of 4 novel C–N bonds was observed
(product 3ab). In order to further demonstrate the practical
performed at 60 1C, b at ambient temperature. c Structure of the major
regioisomer is shown. d 2-Nitroso-5-methyl-pyridine (2 equiv.) was used,
yield is given for a mixture of di- and monoadduct with a ratio of 8 : 1.
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utility of this method, we carried out the reaction between
nitrosopyridine 1a and 2a (Scheme 1) at 4 mmol scale. Product
3a was obtained in 75% yield.
After elucidation of the scope of various alkynes, we further tested
alkenes under the developed reaction conditions. To our delight we
found that 2-methyl-6-nitrosopyridine reacts with a-methylstyrene to
give the product of the ene-reaction (Scheme 3, 4a). A dramatic
improvement of the yield to 93% was observed using HFIP as solvent
compared to previous literature results for a-methylstyrene.5c Nota-
bly, the reaction of 4-methyl-6-nitrosopyridine with cis-stilbene gave
product 3b by annulation and subsequent in situ oxidation, most
probably caused by aerial oxygen. Finally, the annulation also occurs
when 3-methyl-6-nitrosopyridine reacts with a-phenylstyrene. The
target product 4b was isolated with 85% yield.
Scheme 4 Scope of deoxygenation a in CH3CN at 125 1C for 6 h, b in
MeCN at 140 1C for 12 h, and c in EtCN at 150 1C for 12 h.
Finally, we decided to explore the cleavage of N–O bonds to
obtain the corresponding imidazo[1,2-a]pyridines (5). We were
delighted to find that N-oxides could be deoxygenated to the
corresponding imidazo[1,2-a]pyridines upon heating in a sealed tube
(Scheme 4, 5a–5c).16 While the 2,3-phenyl substituted N-oxide (3a)
required around 125 1C, C2-unsubstituted and alkyl-substituted
N-oxides required higher temperatures of 140 1C and 150 1C,
respectively (compounds 5b and 5c). This provides an atom-
economic, efficient metal-free access to variably substituted
imidazo[1,2-a]pyridines. Considering the versatility of the devel-
oped method (broad scope), efficiency (high yields) and generally
excellent regioselectivity of the annulation process, this two-step
operationally simple methodology can be used to access a great
variety of pharmaceutically important imidazo[1,2-a]pyridines.15
A proposed mechanism for the annulation is described in
Scheme 5. The developed transformation proceeds smoothly in
the presence of a radical trap. Furthermore, in competition
experiments, electron rich alkynes react faster in comparison to
electron poor (see ESI† for details). The nitroso group can be
activated by the abundantly present solvent HFIP through
hydrogen bonding for the nucleophilic attack by p-electrons
of the alkyne to generate cation 6. This extremely reactive
species is promptly attacked by the nucleophilic nitrogen of
the pyridine to furnish the N-oxide product 7. This mechanism
also explains the observed regioselectivity in the case of unsym-
metrical alkynes where the vinyl cation is generated at the
Scheme 5 Proposed mechanism for annulation.
benzylic position of the electron-rich substituent due to more
efficient stabilization. At the same time, the failure of alkyl
substituted alkynes in this reaction can also be explained by the
potential lack of cationic stabilization for intermediate 6 in
those cases.
In conclusion, we have developed a novel metal-free annulation
between 2-nitrosopyridines and alkynes to provide challenging
N-oxides in high yields under mild, reagent- and catalyst-free
reaction conditions. A diverse range of alkynes and variably sub-
stituted 2-nitrosopyridines were found to be compatible to the
developed reaction conditions. The products can be obtained with
high regioselectivity. It is notable that the regioselectivity of alkyne
annulation is opposite to metal-catalyzed methods, which allows
obtaining different regioisomers. Therefore, the developed method
is complementary to metal-catalyzed processes. The high functional
group tolerance indicates that the developed method can be used
for complex substrates. The N–O bond in the obtained products
can be easily cleaved upon heating to obtain the corresponding
imidazo[1,2-a]pyridines which represent another important utility
of this newly developed protocol. Furthermore, the application of
alkenes in annulation with 2-nitrosopyridines was demonstrated.
We gratefully acknowledge Prof. Dr Herbert Waldmann for
his generous support.
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