Synthesis of 3-Keto Pyridines from the Conjugated Allenone – Alkynylamine Oxidative Cyclization Catalyzed by Supported Au Nanoparticles

Article abstract of DOI:10.1002/adsc.201901451

Recyclable supported Au nanoparticles on TiO₂ catalyze the cyclization of N-propargyl or N-homopropargyl β-enaminones followed by dehydrogenation (aromatization) leading to substituted 3-keto pyridines or 4-picolines in very good yields. This pathway is in contrast to their known cyclization in the presence of Au(I) or Au(III) catalysts which provides 1,4-oxazepines, instead. The enaminones are formed in situ upon mixing a conjugated allenone or allenyl ester with the alkynylamine, thus the pyridine-forming transformation is typically a one pot process. (Figure presented.).

Full text of DOI:10.1002/adsc.201901451

Title: Synthesis of 3-Keto Pyridines from the Conjugated Allenone –
Alkynylamine Oxidative Cyclization Catalyzed by Supported Au
Nanoparticles
Authors: Manolis Stratakis, Michael Fragkiadakis, Marios Kidonakis,
and Leandros Zorba
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901451
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10.1002/adsc.201901451
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of 3-Keto Pyridines from the Conjugated Allenone –
Alkynylamine Oxidative Cyclization Catalyzed by Supported
Au Nanoparticles
Michael Fragkiadakis,a Marios Kidonakis,a Leandros Zorbaa and Manolis Stratakisa,*
aDepartment of Chemistry, University of Crete, Voutes 71003 Heraklion, Greece, E-mail: stratakis@uoc.gr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
These modes of reactivity were rather unanticipated,
given that the same transformations are also smoothly
catalyzed by cationic variants of metals as activating 
acids, e.g. Au(I) or Au(III).[10] However, it has been shown
theoretically that a neutral Au(0) cluster can strongly
interact to an alkyne, and the triple bond is activated
toward nucleophilic attack, with the magnitude of  back-
donation in the triple bond – Au interaction to be more
significant than  donation.[11]
Abstract. Recyclable supported Au nanoparticles on
TiO2 catalyze the cyclization of N-propargyl or N-
homopropargyl
-enaminones
followed
by
dehydrogenation (aromatization) leading to substituted
3-keto pyridines or 4-picolines in very good yields. This
pathway is in contrast to their known cyclization in the
presence of Au(I) or Au(III) catalysts which provides
1,4-oxazepines, instead. The enaminones are formed in
situ upon mixing a conjugated allenone or allenyl ester
with the alkynylamine, thus the pyridine-forming
transformation is typically a one pot process.
Our latest report, regarding the smooth Au/TiO2-
catalyzed cycloisomerization of conjugated allenones into
furans,[8c] urged us to examine the possible Au-catalyzed
cyclization of N‑ propargylic ‑ enaminones (N-1,5-
enynes),[12] compounds that could be formally obtained
from an uncatalyzed reaction between allenones and
Keywords: Au nanoparticles; heterogeneous catalysis;
cyclization; N-alkynyl -enaminones; pyridines
propargylamine.[13]
Indeed,
propargylamine
adds
Supported Au(0) nanoparticles (Au NPs) have been proven
as
excellent
catalysts
in
cycloisomerization
quantitatively to the model allenone 1 in dioxane as solvent
within 10 min at 25 oC, yielding exclusively the (Z)-
enaminone 1′. The observed Z-geometry is in accordance
to similar enaminones in the literature.[14] The possible Au
NP-catalyzed cyclization of N-1,5-enyne 1′ was then
examined (Scheme 2). While no reaction was seen under
refluxing conditions in low boiling point solvents (e.g.,
DCM, THF), to our delight, in the presence of Au/TiO2 (2
transformations, where the activation of sp-carbon  bonds
(alkynes or allenes) on the low coordinated electrophilic
Au atoms at the corners or edges of nanoparticles[1]
triggers intramolecular nucleophilic attack by carbon
nucleophiles (Scheme 1).[2] Thus, simple 1,6-enynes,[3] N-
((1H-indol-3-yl)methyl)propiolamides (N-1,6-enynes),[4]
aryl propargyl ethers,[5] or -alkynylfurans[6] undergo
cyclization in the presence of catalytic amounts of
supported Au nanoparticles. In addition, the activation of
an alkyne or allene by Au NPs may trigger inter or
intramolecular nucleophilic attack by nitrogen,[7] oxygen,[8]
or other[9] nucleophiles.
o
mol%) and refluxing toluene as solvent (110 C), 1′ was
completely converted into 3-keto pyridine 1a after 12 h,
which was isolated after column chromatography in 80%
isolated yield.[15] In various other solvents, and at lower
temperatures around 70-80 oC (including toluene) the
cyclization proceeds sluggishly (up to 15% after 20 h). No
5-membered ring product (pyrrole) was formed from a
possible 5-exo cyclization mode. Notably, the catalytic
cyclization of N‑ propargyl ‑ enaminones in the presence
of Au(I) or Au(III) substances leads to 1,4-oxazepines, via
a 7-exo-dig pathway[16] (Scheme 2), or to 5-membered ring
3-methylene-1-pyrrolines in the presence of arynes and a
Au(I) catalyst.[17] The structurally similar N-tosyl-N-
propargyl enaminones lead to pyrroles using homogeneous
Au(I) catalysts.[18] In this case it was suggested that
cyclization is preceded by an amino-Claisen rearrangement
forming an intermediate -allenyl -enaminone. As the
uncatalyzed reaction of formation of the N-propargyl
enaminone 1′ is very fast, we were able to achieve the
synthesis of keto pyridine 1a in a simple one pot operation.
Scheme 1. Selected examples of cycloisomerization
reactions catalyzed by Au/TiO2 from our group.
1
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10.1002/adsc.201901451
Advanced Synthesis & Catalysis
Thus, premixing 1 equiv of allenone with 1.1 equiv of
propargylamine in toluene at 25 C for 10 min, and then
adding the catalyst followed by heating, resulted to the
same outcome, as in the case of using directly 1′. In fact,
premixing the reactants for 10 min is more than enough,
CuBr, pyridines are formed in moderate to good yields, yet
under catalysis by a base, pyrroles were seen, instead.[21]
Cyclization/aromatization has been achieved using
stoichiometric amounts of CuI, as the oxidation of the
cyclization products (dihydropyridines) into pyridines is
not catalytic, with Cu(I) being reduced into Cu(0).[22] If the
N atom of N-propargyl enaminones is trisubstituted, 1,6-
dihydropyridines can be also formed in the presence of a
Cu(I)-catalyst (3-10 mol%).[23] Similar results were
obtained in the presence of AgNO3 (10 mol%).[24] Using
CuCl2 (20 mol%) and a base, N-propargyl enaminones
cyclize into pyrroles.[25] Finally, with stoichiometric
amounts of ZnCl2, the cyclization leads to the 7-membered
ring 1,4-oxazepines.[26] Apart from the metal-catalyzed
protocols, upon treatment with a base in the presence of a
suitable nucleophile or electrophile, N-propargyl
enaminones lead to substituted pyridines,[27] but not to 3-
keto pyridines, as in our case.
o
otherwise unreacted allenone
1
should had been
instantaneously isomerized by Au/TiO2 into 2-(p-
tolyl)furan.[8c] The catalytic system (Au/TiO2) is recyclable
o
by simple filtration, washing and drying at 90 C for 2 h. It
was reused in five consecutive runs with little loss of
activity. Thus, in the 5th run, the reaction took 15 h to go to
completion, which is attributed to the partial loss of
catalyst in each recycling procedure. As a further evidence
of the heterogeneous nature of our transformation, we
found that the cyclization of N-propargyl enaminones does
not proceed at all in the hot filtrate of another cyclization
reaction, which implies that Au leaching into the solution
is essentially minimal, if any.
Scheme 2. The Au/TiO2-catalyzed cyclization of a model
compound 1′, and the known[16] Au(I) or Au(III)-catalyzed
cyclization of N‑ propargylic ‑ enaminones.
The transformation 1′  1a indicates that Au NPs
activate the alkyne that then is susceptible to a 6-endo
nucleophilic attack by the enaminone double bond leading
to intermediate I (Scheme 3). This intermediate could
Scheme 3. Possible mechanisms in the Au-catalyzed
formation of 3-keto pyridine 1a from N-propargyl
enaminone 1′.
undergo
protodeauration,
which
releases
the
Having optimized the reaction conditions (2 mol%
Au/TiO2, toluene as solvent, 110 C), we examined the
dihydropyridine II from the chemisorbed species I and
regenerates the catalyst. We could not, however, detect II
by GC-MS at any stage of the reaction, which possibly
implies that the dehydrogenation of the dihydropyridine (or
any isomer of it) into pyridine 1a may occur faster than the
initial cyclization. Alternatively and more likely,
o
scope and limitations of this transformation. Thus mixing a
series of conjugated allenyl ketones (1 equiv) with 1.1
equiv of propargylamine for 10 min and then adding the
catalyst, followed by heating for a certain period of time,
we found that the reaction is general. The isolated yields of
pyridines are very acceptable and vary between 65-80%
(Table 1). Using aryl substituted internal propargylamines,
formation of pyridines also occurs readily under the same
reaction conditions, despite the substantial increase of
bulkiness on the triple bond. Note that, apart from
conjugated allenones, allenyl esters work equally well
(products 18a, 19a and 19b).
Regarding allenones, the only non-productive
substrates are those having a substituent at the germinal
position with respect to the carbonyl group (see the bottom
part of Table 1). Such substituents generate a quaternary
center in the possible intermediate I, and thereby it cannot
be aromatized into III (see the proposed mechanism in
Scheme 3). Additionally, secondary propargyl amines (R =
chemisorbed
I could undergo dehydrogenation into
aromatic III, which after protodeauration should lead
directly into 1a. As the reaction, also takes place with the
same rate under inert conditions, we conclude that the
dehydrogenation of intermediate I (Scheme 3) is an
acceptorless H2 elimination process. Preceding relevant
examples of Au NP-catalyzed dehydrogenations are well
known in the case of 1,2-dihydroquinolines, that are
oxidized into quinolines in the presence of Au/TiO2.[19] In
intermediate I we consider partial and not full charges,
based on previous calculations on the bonding nature of
chemisorbed intermediates on Au clusters.[20]
The cyclization of N-propargyl enaminones by other
catalytic systems is known so far only under homogeneous
catalysis conditions and can lead either to 5- or 6-
membered ring products. In the presence of 20-40 mol%
-CH2CCH or Me) do not lead to cyclized products
2
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10.1002/adsc.201901451
Advanced Synthesis & Catalysis
Table
1.
Synthesis
of
pyridines
from the
In this case a hypothetical alkyldeauration would be an
unfavorable process to occur.
cyclization/dehydrogenation of in situ generated N-
propargyl enaminones catalyzed by Au/TiO2.a
Scheme 4. The Au-catalyzed oxidative cyclization of an
allenone with homopropargylamine and
mechanism.
a proposed
Table
2.
Synthesis
of
4-picolines
from
the
cyclization/dehydrogenation of in situ generated N-
homopropargyl enaminones catalyzed by Au/TiO2.a
aIsolated yields after chromatography (0.2 mmol scale).
Following the very fruitful results of the synthesis of
pyridines using propargylamines,[28] we then examined the
aIsolated yields after chromatography (0.2 mmol scale). b77%
yield in 1.0 mmol scale.
parent homopropargylamine (HCCCH2CH2NH2). In this
case a 6-exo cyclization pathway in the corresponding N-
homopropargyl enaminones could lead to 3-keto 4-
(bottom part of Table 1), despite the fact that the
corresponding N-propargyl enaminones are readily formed.
3
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10.1002/adsc.201901451
Advanced Synthesis & Catalysis
We thank professor I. N. Lykakis for fruitful discussions and for
obtaining the HRMS spectra of the unknown compounds.
picolines. Indeed, the acyclic enaminones are readily
formed (see compound 1′′ as a typical example in pages
43-44 of the Supporting Information), and are cyclized in
the presence of 2 mol% Au/TiO2, forming the 4-
methylpyridines (4-picolines) in very good isolated yields.
Our proposed mechanism appears in Scheme 4, in which
most likely intermediate IV is dehydrogenated into V and
after protodeauration the 3-keto 4-picoline is released. In
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allenone or allenyl ester in toluene (0.5 mL) are added 0.22
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oC, Au/TiO2 (74 mg, 2.0 mol% in Au) is added and the
o
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until the reaction was complete (see Figures 1 and 2). The
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mg (1.0 mmol) of allenone 1, 71 L of propargylamine
(1.1 mmol), toluene (3 mL) and Au/TiO2 (370 mg, ~3.7 mg
of Au, as the catalyst contains 1 w/w% Au). After 12 h at
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5
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10.1002/adsc.201901451
Advanced Synthesis & Catalysis
UPDATE
Synthesis of 3-Keto Pyridines from the
Conjugated Allenone – Alkynylamine Oxidative
Cyclization Catalyzed by Supported Au
Nanoparticles
Adv. Synth. Catal. Year, Volume, Page – Page
Michael Frangiadakis, Marios Kidonakis, Leandros
Zorba and Manolis Stratakis*
6
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