Metal-Free Synthesis of Highly Substituted Pyridines by Formal [2+2+2] Cycloaddition under Mild Conditions

Article abstract of DOI:10.1002/anie.201606604

The synthesis of pyridines through direct intermolecular cycloaddition of alkynes and nitriles is a contemporary challenge in organic synthesis. A Br?nsted acid mediated formal [2+2+2] cycloaddition of heteroalkynes and nitriles was developed that proceed

Full text of DOI:10.1002/anie.201606604

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International Edition: DOI: 10.1002/anie.201606604
German Edition: DOI: 10.1002/ange.201606604
Cycloaddition
Metal-Free Synthesis of Highly Substituted Pyridines by Formal
[2+2+2] Cycloaddition under Mild Conditions
Lan-Gui Xie+, Saad Shaaban+, Xiangyu Chen, and Nuno Maulide*
Abstract: The synthesis of pyridines through direct intermo-
lecular cycloaddition of alkynes and nitriles is a contemporary
challenge in organic synthesis. A Brønsted acid mediated
formal [2+2+2] cycloaddition of heteroalkynes and nitriles
was developed that proceeds under mild conditions. This
constitutes a modular approach to highly substituted pyridine
cores.
A
mong the aromatic heterocycles, the pyridine ring plays
a central role in both natural product chemistry and synthetic
pharmaceutical chemistry.[1] Consequently, the development
of synthetic methods to access these motifs has attracted
extensive interest. Condensation reactions, represented by
the classical Hantzsch, Chichibabin, and Krçhnke reactions,
represent the most widespread approach in the synthetic
library.[2] Over the past decade, a number of alternative
strategies have also been documented, along with investiga-
tions focusing on transition-metal catalysts and organocata-
lysts.[3]
Nevertheless, when compared to these strategies, the
direct [2+2+2] cycloaddition of two readily available alkynes
and a nitrile remains perhaps the most atom-economical and
straightforward tool to access complex pyridine building
blocks.[4,5] The considerable enthalpic and entropic penalty of
bringing the three reaction partners together has dictated that
most studies on this cross-trimerization reaction have been
centered on the development of metal catalysts,[6] whilst
chemo- and regioselectivity remains a largely unsolved issue
(Scheme 1c). Among the few metal-free [2+2+2] cycloaddi-
tions described,[7] Movassaghi reported an elegant enamide-
based strategy employing electron-rich olefins as annulation
partners (Scheme 1a). The uncatalyzed formal cycloaddition
of tethered cyanodiynes to fused pyridines by Sakai and
Danheiser (Scheme 1b) probably represents the state of the
art. This thermal transformation, based on purely intra-
molecular cascade reactions, mandates the prior multistep
synthesis of the cyanodiyne substrates and requires temper-
atures higher than 1158C to proceed.[8a,b]
Scheme 1. Previous milestone by Movassaghi and Danheiser, and
a proposed intermolecular [2+2+2] cycloaddition en route to pyri-
dines.
tethered intermediate B. Such an intermediate would be
poised to undergo a formal cycloaddition, leading to the
corresponding pyridine product 3. Herein, we report a metal-
free intermolecular [2+2+2] cycloaddition of simple precur-
sors to access pentasubstituted and highly functionalized
pyridine cores that proceeds under mild conditions.
At the onset of our studies, we evaluated the reaction of
thioalkyne 1a with alkynenitrile 2a (Table 1). Although the
mechanistic hypothesis above (Scheme 1) postulates the need
for only catalytic amounts of acid, only traces of pyridine
product were observed when using 0.2 equiv of TfOH
(entry 1). We were pleased to detect product 3a in 72%
yield when using stoichiometric amounts of acid (entry 2).
The amount of thioalkyne and TfOH was lowered to
1.1 equiv, leading to better yields of 3a (entry 4). Concen-
tration was also shown to play an important role in this
process (entry 5).
We envisioned that a simple cyanoalkyne (2; Scheme 1d)
might reversibly intercept a stabilized keteniminium or
ketenethionium (A), generated in situ through the protona-
tion of an electron-rich alkyne (1),[9–12] to form an active
[*] Dr. L.-G. Xie,[+] S. Shaaban,[+] Dr. X. Chen, Prof. Dr. N. Maulide
University of Vienna, Institute of Organic Chemistry
Wꢀhringer Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
[+] These authors contributed equally to this work.
With suitable conditions in hand, we next examined the
scope of this pyridine synthesis by using various thioalkynes
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201606604.
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Table 1: Optimization of the synthesis of 3a.[a]
Entry
x
y
z
Concentration
Yield [%][b]
1
2
3
4
5
1.1
1.5
1.1
1.1
1.1
1.0
1.0
1.0
1.0
1.0
0.2
1.5
1.5
1.1
1.1
0.05 m
0.05 m
0.05 m
0.05M
0.1 m
Trace
72
70
78
62
[a] Reactions were conducted on a 0.2 mmol scale. For details, see the
Supporting Information. [b] Yield of isolated product.
1 in conjunction with alkynylnitrile 2 (Scheme 2). Cyclo-
propyl and cyclopentyl substrates could be incorporated into
the pyridine products (3b and 3c) in 37% and 62% yield.
We also tested the reactions of different thioalkynes, in
which an aryl appendage carries different substituents in
varied positions (3d–3e).
Scheme 3. Scope of the reaction with ynamides.[a] [a] Reactions were
conducted on a 0.2 mmol scale. The yield of isolated product is
shown. NPG=nitrogen-protecting group.
ynamides, furnishing the heterocycles 5a–c and 5 f–h in good
to excellent yields.
With a tosyl-protected ynamide, the reaction proceeded
smoothly as well (5d and 5i). Heteroatom-tethered cyanoal-
kynes are also amenable to this transformation, leading to the
furopyridines 5e and 5g. The 7-membered bicyclopyridine 5l
can also be prepared in moderate yield. Very good yields are
observed for cyanoalkynes carrying aryl groups (5m,n) or
vinyl groups (5o,p), as well as cholesterol derivative 5q.
Interestingly, the use of halogen-substituted cyanoalkynes
6 led to halogenated pyridines. As seen in Scheme 4, different
halogenated cyanoalkynes carrying I, Br, or Cl reacted
productively with different ynamides to furnish pyridine
moieties 5r–5z in good to moderate yields. In addition,
thioalkynes with the corresponding halogen-substituted cya-
noalkynes 6 led to the corresponding pyridine cycle (5aa)
with a relatively lower yield.
The ultimate challenge in these transformations would be
a fully intermolecular [2+2+2] combination of two non-
tethered alkynes and a nitrile.[13] Such a transformation is
hardly possible in regioselective manner even under transi-
tion-metal catalysis.[8c] In the event, we found that product 8
could be synthesized by treating 1.0 equiv of 1 f and 2.0 equiv
of nitrile 7 with 0.5 equiv of TfOH at room temperature
(Scheme 5).
Scheme 2. Scope of the synthesis of pyridines from thioalkynes.[a]
[a] Reactions were conducted on a 0.2 mmol scale. NMR yields with
DMAP as internal standard are shown. DCM=dichloromethane.
This method is also well suited for the introduction of an
additional arene ring along the tether, as illustrated by the
synthesis of tricyclic pyridines 3 f,g. A vinyl-substituted
alkynylnitrile furnished the corresponding alkenylpyridine
3h in good yield. A terminal cyanoalkyne can also be
employed, and product 3i was produced in 47% yield.
Importantly, the reaction was also applicable to the synthesis
of the six-membered-ring-fused pyridine 3k, as well as ether-
linked pyridine 3j.
Subsequently, a broad range of ynamides 4 were subjected
to this formal cycloaddition (Scheme 3) to afford the desired
substituted pyridines in good to excellent yields. The reaction
proceeds smoothly with alkyl- and (hetero)aryl-substituted
The products contain reactive handles for further manip-
ulation.[14] In particular, the halopyridines shown in Scheme 4
2
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substrate scope with respect to both reaction partners. The
modularity and simplicity of the reagents, combined with the
mild reaction conditions and low temperatures, conspire to
make this a powerful and appealing method for the rapid
assembly of substituted pyridine structures.
Acknowledgements
We are grateful to the University of Vienna, the Deutsche
Forschungsgemeinschaft (Grant MA 4861/1-2) and the ERC
(StG 278872, FLATOUT) for support of this work. Crystallo-
graphic analysis by Ing. A. Roller (U. of Vienna) is acknowl-
edged.
Keywords: alkynes · cycloaddition · heteroalkynes · nitriles ·
pyridines
Scheme 4. Scope of the reaction with halogen-containing cyanoal-
kynes.[a] [a] Reactions were conducted on a 0.2 mmol scale. The yield
of isolated product is shown.
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Scheme 5. Intermolecular formal [2+2+2] cycloaddition to form pyri-
dine 8.
appear to be ideally suited for cross-coupling reactions, as
exemplified in Scheme 6a.
Finally, the (methylthio) moiety of pyridines such as 3a
can be readily hydrogenated in the presence of Raney Nickel
(Scheme 6b).
In summary, we have developed a Brønsted acid pro-
moted, metal-free formal [2+2+2] intermolecular cycloaddi-
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conditions. The reaction displays generality and a broad
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Scheme 6. Derivatization of products: cross-coupling and reduction.
THF=tetrahydrofuran, TMS=trimethylsilyl.
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Received: July 7, 2016
Revised: July 22, 2016
Published online: && &&, &&&&
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Communications
Cycloaddition
L.-G. Xie, S. Shaaban, X. Chen,
N. Maulide*
&&&& — &&&&
Metal-Free Synthesis of Highly
Substituted Pyridines by Formal [2+2+2]
Cycloaddition under Mild Conditions
When 2+2+2=p: The synthesis of
pyridines through direct intermolecular
cycloaddition of alkynes and nitriles is
a contemporary challenge in organic
synthesis. A Brønsted acid mediated
formal [2+2+2] cycloaddition of hetero-
alkynes and nitriles was developed that
proceeds under mild conditions. This
constitutes a modular approach to highly
substituted, densely functionalized pyri-
dine cores.
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