Visible-Light-Promoted [2 + 2 + 2] Cyclization of Alkynes with Nitriles to Pyridines Using Pyrylium Salts as Photoredox Catalysts

Article abstract of DOI:10.1021/acs.orglett.7b00292

A highly regioselective [2 + 2 + 2] cyclization of aromatic alkynes with nitriles is developed for the preparation of 2,3,6-trisubstituted pyridines under visible-light irradiation using a pyrylium salt as the photoredox catalyst. This cycloaddition is ac

Full text of DOI:10.1021/acs.orglett.7b00292

Letter
pubs.acs.org/OrgLett
Visible-Light-Promoted [2 + 2 + 2] Cyclization of Alkynes with Nitriles
to Pyridines Using Pyrylium Salts as Photoredox Catalysts
†
,†
,†,‡
Kuai Wang, Ling-Guo Meng,* and Lei Wang*
†
Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P.R. China
‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P.R. China
*
S Supporting Information
ABSTRACT: A highly regioselective [2 + 2 + 2] cyclization of aromatic alkynes with nitriles is developed for the preparation of
,3,6-trisubstituted pyridines under visible-light irradiation using a pyrylium salt as the photoredox catalyst. This cycloaddition is
2
achieved through a photooxidative single-electron-transfer process at room temperature and under metal-free conditions. A
variety of aromatic alkynes and nitriles are employed to furnish the annulation products in good yields.
he search for a facile synthetic strategy to obtain pyridine
skeletons using easily available starting materials is an
Scheme 1. [2 + 2 + 2] Cycloaddition Routes to Pyridines
T
interesting challenge for organic chemists because the pyridine
core is widespread in natural compounds, such as nicotinamide
1
and vitamin B , with a variety of biological activities.
6
Meanwhile, this azaheterocyclic skeleton is regarded as an
important molecular target due to its diverse applications in the
2
3
field of chemistry, including catalysis, functional materials,
4
5
6
pharmaceuticals, pesticides, and other uses. Until now, many
metal-catalyzed synthetic tactics, such as C−H activation,
rearrangement, ring-expansion, and multicomponent reac-
7
8
9
10
1
1
tions, have been developed for the formation of pyridines. In
addition to the above reaction modes, transition-metal-
12
catalyzed cycloadditions, especially the intramolecular [2 +
+ 2] annulation, have been proven as an effective route to
2
13
pyridines (Scheme 1a). A significant breakthrough for the
construction of pyridines has been the direct transition-metal-
catalyzed [2 + 2 + 2] annulations of alkynes and nitriles in a 2:1
14
ratio because of the simplicity of the method. For example,
Takahashi reported a reaction of internal alkynes and nitriles to
form pyridines in the presence of a bimetallic system (Scheme
1
5
1
b). Furthermore, Obora achieved an intermolecular [2 + 2 +
]-cross-cycloaddition using aliphatic terminal alkynes to form
their superiority in terms of mild reaction conditions, and they
have been used as a powerful platform for the construction of
2
pyridines, with low chemoselectivity in most cases (Scheme
18,19
1
6
target molecules.
But there have been a few related to the
1
c). Although there have been a few reports on the
20
synthesis of pyridine cores. Very recently, we reported a
direct method for the generation of 4-aryl tetralones via a
visible-light induced cyclization of styrenes with molecular
intermolecular [2 + 2 + 2] cyclizations of aromatic terminal
alkynes with nitriles to pyridines, the reactions could not occur
1
7
without the use of a metal catalyst. Therefore, the
development of more facile and environmentally benign
protocols for the synthesis of pyridines from aromatic terminal
alkynes is highly desirable, especially under metal-free
conditions.
21
oxygen. In order to further explore other photoinduced
cycloadditions, our attempts used alkynes as the substrate for
producing cyclic compounds. After comparison of the oxidative
Most recently, photoinduced and photosensitized organic
Received: February 11, 2017
transformations have received considerable attention due to
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00292
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
potential of alkenes with alkynes, a pyrylium salt with higher
oxidative power could be used as photocatalyst for promoting a
not palpably change when the reaction was performed under an
N atmosphere (entry 9), which indicated that N was not
2
2
22
new reaction under visible-light irradiation. To our delight, a
highly regioselective [2 + 2 + 2] annulation of aromatic alkynes
with nitriles to form 2,3,6-trisubstituted pyridines under visible-
light irradiation using the pyrylium salt as the photoredox
catalyst was developed (Scheme 1d). Although 2,4,6-triarylpyr-
idines have been synthesized from the reaction of aryl ketones
and benzylamines using eosin Y as the photoredox catalyst
involved in the reaction and was not the source of the nitrogen
atom in the pyridines. When an oxygen atom was replaced by a
sulfur atom in TPPT, no improved result was obtained (entry
10). Further investigation on the use of other organic
photosensitizers showed that eosin Y, rose bengal, rhodamine
B, and acridinium salt were not effective photocatalysts for the
reaction.
Having the optimized reaction conditions in hand, the
generality of this [2 + 2 + 2] cyclization protocol was
investigated as shown in Scheme 2. For a range of aromatic
23
under visible-light irradiation, the preparation of the pyridine
nucleus from alkynes and nitriles through organocatalytic [2 +
24
2
+2] methodology has rarely been investigated. Herein, we
report this pyrylium-catalyzed and photoinduced [2 + 2 + 2]
cyclization of two aromatic alkynes with a nitrile to 2,3,6-
trisubstituted pyridines under metal-free conditions.
a,b
Scheme 2. Scope of the Aromatic Alkynes
At the outset, a solution of phenylacetylene (2a) and 2,4,6-
triphenylpyrylium tetrafluoroborate (TPPT) in CH CN (1a,
3
excess) was irradiated with blue light under various conditions,
and the results are listed in Table 1. After the reaction was
a
Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: aromatic alkyne (2, 0.40 mmol), CH CN (1a,
3
2
.0 mL), T(p-Cl)PPT (0.06 mmol), blue LED, sealed tube, room
b
c
temperature, 12 h. Isolated yield. Reaction for 6 h.
alkynes with either an electron-rich substituent (Me, Et, Pr, Bu,
t
and Bu) or an electron-poor substituent (F, Cl, and Br) on the
a
phenyl rings, the reactions proceeded smoothly to generate the
corresponding products (3aa−ak) in moderate to good yields.
When the model reaction was performed on a larger scale (4.0
mmol phenylacetylene), a 56% yield of 3aa was obtained.
There was no obvious electronic induction effect on the
formation of 3ab−af and 3ai−ak. When 1-ethynyl-2-methyl-
Reaction conditions: phenylacetylene (2a, 0.40 mmol), CH CN (1a,
3
2
.0 mL), photocatalyst (0.06 mmol), sealed tube, room temperature,
b c d
light irradiation for 12 h. Isolated yield. NR = no reaction. Under
N .
2
performed in a sealed tube at room temperature for 12 h,
benzene was reacted with CH CN under the standard reaction
3
pyridine derivative 3aa was generated as a colorless solid in
conditions, a 40% yield of the desired product 3ah was
obtained owing to the steric effect (3ah vs 3ab and 3ag).
Meanwhile, a probable product was not generated via the 1,5-
hydrogen atom transfer process. Notably, 1,4-diethynylbenzene
was also converted to the corresponding product (3al) in 60%
yield by shortening the reaction time to maximize the
avoidance of the probable alkyne’s oligomerization; meanwhile,
a trace amount of the bis-[2 + 2 + 2] cyclic product was
detected by HRMS. Further, this bis-[2 + 2 + 2] cyclic reaction
did not become the main reaction when the amount of the
catalyst was increased or the reaction time was prolonged.
When an aliphatic terminal alkyne (e.g., 1-pentyne) or internal
alkyne, such as 1-phenyl-1-propyne or diphenylacetylene, was
used as one of the substrates in the reaction, the corresponding
products were detected in trace amounts due to their lower
reactivity. In addition, diynes (1,6-heptadiyne and 1,7-
diphenylhepta-1,6-diyne) failed as substrates in the reaction.
It should be noted that we could not observe correlative
4
2% yield via a [2 + 2 + 2] cycloaddition process (entry 1), and
its structure was determined by NMR spectroscopy and HRMS
1
7a
analysis.
demonstrated that the blue LED was the best choice (entries
and 3). No obvious effect was observed after the anion of the
A survey of different color light sources
2
−
−
catalyst was changed from BF4 to CF SO (entry 4 vs 1).
3
3
Other pyrylium salts were examined, and the results indicated
that substituents on the pyrylium salts played an important role
in the reaction. Pyrylium salts with an electron-donating group
(MeO or Me) displayed decreased catalytic efficiency in the
reaction (entries 5 and 6). Meanwhile, pyrylium salts with an
electron-withdrawing group (F or Cl) gave a better yield of the
product (entries 7 and 8). Among the tested pyrylium salts,
2,4,6-tris(4-chlorophenyl)pyrylium tetrafluoroborate [T(p-Cl)-
PPT] exhibited the highest catalytic reactivity, and the
determined oxidative and reductive potentials of pyrylium
salts are shown in the Supporting Information. The yield did
B
DOI: 10.1021/acs.orglett.7b00292
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
byproducts or detections to show the existence of the alkyne’s
polymerization.
To further extend the substrate scope of this [2 + 2 + 2]
cycloaddition, a variety of nitriles with aromatic alkynes were
examined under the optimal reaction conditions, and the results
are listed in Scheme 3. Aliphatic nitriles with different lengths
related control experiments were conducted. The yield was
improved by using different pyrylium salts, and T(p-Cl)PPT,
which had the highest oxidative power, gave the best yield.
When (4-nitrophenyl)acetylene, which has a high oxidation
potential, was reacted with 1a, none of the corresponding
pyridine was obtained. Comparing the product yields with
+
other organic photosensitizers (TCB, Mes-Acr , eosin Y, rose
a,
b
18a
Scheme 3. Scope of the Nitriles
bengal, and rhodamine B) that had low potentials to the
yield of 3aa obtained using T(p-Cl)PPT indicated that a
photooxidative single-electron-transfer process was occurring
during the formation of the pyridines.
On the basis of the above mechanistic investigations and the
reported literature, a possible mechanism for this [2 + 2 + 2]
cycloaddition was proposed, as shown in Scheme 4. A single
Scheme 4. Proposed Mechanism
a
electron-oxidation of alkyne 2a (Eox = +2.163 V) to form
radical cation A in the presence of the excited state of T(p-
Cl)PPT (E1/2 * = +2.3 V) as the photocatalyst could be
Reaction conditions: 2 (0.40 mmol), RCN (1, 2.0 mL), T(p-Cl)PPT
(
0.06 mmol), blue LED, sealed tube, room temperature, 12 h (For
b
red
NCCH CH CN in 10 equiv, 2.0 mL of DCE as solvent). Isolated
yield.
2
2
accomplished by comparing the oxidation potential of the
reactants. Furthermore, the existence of intermediate A could
be shown in the reaction process by the control experiments, as
shown in the Supporting Information. The formed intermediate
A reacted with the nitrile (1a) to generate intermediate B,
which underwent addition to another equivalent of 2a to afford
intermediate C. Then the formed C converted to pyridinium
radical cation D via a single-electron transfer process. Finally, a
of carbon chains, including butyronitrile, isobutyronitrile,
valeronitrile, and isovaleronitrile, could be reacted with
aromatic alkynes to produce the corresponding 2,3,6-
trisubstituted pyridines (3ba−ea, 3bb−eb, and 3bj−ej) in
moderate to good yields. The efficiency of the reaction was
slightly sensitive to the length of carbon chain, which could be
ascribed to steric hindrance (3ba vs 3da; 3ca vs 3ea).
Cyclopropanecarbonitrile and cyclohexanecarbonitrile reacted
with 2a to give 3fa and 3ga in 62% and 50% yields, respectively.
Meanwhile, a nitrile containing an ester group, ethyl 2-
cyanoacetate, proceeded well in the reaction with 2a, providing
the corresponding product (3ha) in 55% yield. Furthermore,
the reactions of deuterated acetonitrile (CD CN) with different
aromatic alkynes afforded the cyclization products (3ia, 3if, and
3
compounds, i.e., succinonitrile and hexanedinitrile, were used as
one of the substrates, they were also compatible with the
present reaction conditions, reacting with the aromatic alkynes
and delivering the products (3ja−jk, 3ka, 3kb, and 3kj) in the
expected yields (53−79%). A similar bis-[2 + 2 + 2] cyclization
reaction was also observed when dicyano compound was
reacted with alkyne. When two different alkynes were tested in
−
single-electron reduction of D by PC provided the desired
product (3aa) with the concurrent regeneration of the
photocatalyst (PC) for the next cycle. On the other hand,
intermediate D also might be converted to 3aa via chain-
propagation electron transfer from another alkyne substrate
25
2
a.
In conclusion, we have developed a practical pyridine
synthesis on the basis of a visible-light promoted photocatalytic
2 + 2 + 2] reaction of aromatic alkynes with nitriles. A wide
3
[
ij) with a CD moiety in 42−52% yields. When dicyano
3
range of functional groups were tolerated under these simple
and mild reaction conditions. Most importantly, a simple and
readily available pyrylium salt proved to be an effective and
novel photocatalyst, thus avoiding the use of transition-metal
catalyst, which is often expensive and requires the use of harsh
reaction conditions. Further efforts to achieve a deeper
understanding of this transformation are currently underway.
the reaction with CH CN under the standard reaction
conditions, a mixture of pyridines was observed by H NMR
and HRMS analysis. It should be noted that aromatic nitriles
were ineffective substrates for the reaction.
To elucidate the reaction mechanism clearly, further and
more careful comparisons (Supporting Information) and
3
1
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00292.
C
DOI: 10.1021/acs.orglett.7b00292
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Full experimental details and characterization data for all
Letter
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Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005, 127, 5030. (f) Kase, K.;
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products (PDF)
2
007, 9, 931.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
(14) Heller, B.; Hapke, M. Chem. Soc. Rev. 2007, 36, 1085.
(15) Takahashi, T.; Tsai, F.-Y.; Kotora, M. J. Am. Chem. Soc. 2000,
22, 4994.
1
E-mail: milig@126.com.
E-mail: leiwang88@hotmail.com.
ORCID
(
16) (a) Satoh, Y.; Obora, Y. J. Org. Chem. 2013, 78, 7771. (b) Chen,
Y.-L.; Sharma, P.; Liu, R.-S. Chem. Commun. 2016, 52, 3187.
(17) (a) Wang, C.; Li, X.; Wu, F.; Wan, B. Angew. Chem., Int. Ed.
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011, 50, 7162. (b) Suzuki, D.; Tanaka, R.; Urabe, H.; Sato, F. J. Am.
Lei Wang: 0000-0001-6580-7671
Notes
Chem. Soc. 2002, 124, 3518. (c) Tanaka, R.; Yuza, A.; Watai, Y.;
Suzuki, D.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005,
1
27, 7774. (d) Senaiar, R. S.; Young, D. D.; Deiters, A. Chem.
Commun. 2006, 1313.
18) (a) Ravelli, D.; Protti, S.; Fagnoni, M. Chem. Rev. 2016, 116,
850. (b) Karkas, M. D.; Porco, J. A., Jr; Stephenson, C. R. J. Chem.
Rev. 2016, 116, 9683. (c) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem.
Rev. 2016, 116, 10035. (d) Prier, C. K.; Rankic, D. A.; MacMillan, D.
The authors declare no competing financial interest.
(
9
ACKNOWLEDGMENTS
■
̈
̈
We gratefully acknowledge the National Natural Science
Foundation of China (21572078, 21372095, 21402061),
Young Talent Key Project of Anhui Province
W. C. Chem. Rev. 2013, 113, 5322. (e) Hari, D. P.; Ko
Chem., Int. Ed. 2013, 52, 4734. (f) Shi, L.; Xia, W. Chem. Soc. Rev.
̈
nig, B. Angew.
(
gxyqZD2016411), and the Natural Science Foundation of
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012, 41, 7687. (g) Xuan, J.; Xiao, W.-J. Angew. Chem., Int. Ed. 2012,
1, 6828. (h) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev.
011, 40, 102. (i) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010,
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Anhui (No. 1708085MB45) for financial support of this work.
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