Visible-Light-Promoted [2 + 2 + 2] Cyclization of Alkynes with Nitriles to

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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 2,3,6-trisubstituted pyridines under visible-light irradiation using a pyrylium salt as the photoredox catalyst. This cycloaddition is 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.

T

Scheme 1. [2 + 2 + 2] Cycloaddition Routes to Pyridines

he search for a facile synthetic strategy to obtain pyridine skeletons using easily available starting materials is an interesting challenge for organic chemists because the pyridine core is widespread in natural compounds, such as nicotinamide and vitamin B6, with a variety of biological activities.1 Meanwhile, this azaheterocyclic skeleton is regarded as an important molecular target due to its diverse applications in the field of chemistry, including catalysis,2 functional materials,3 pharmaceuticals,4 pesticides,5 and other uses.6 Until now, many metal-catalyzed synthetic tactics,7 such as C−H activation,8 rearrangement,9 ring-expansion,10 and multicomponent reactions,11 have been developed for the formation of pyridines. In addition to the above reaction modes, transition-metalcatalyzed cycloadditions,12 especially the intramolecular [2 + 2 + 2] annulation, have been proven as an effective route to pyridines (Scheme 1a).13 A significant breakthrough for the construction of pyridines has been the direct transition-metalcatalyzed [2 + 2 + 2] annulations of alkynes and nitriles in a 2:1 ratio because of the simplicity of the method.14 For example, Takahashi reported a reaction of internal alkynes and nitriles to form pyridines in the presence of a bimetallic system (Scheme 1b).15 Furthermore, Obora achieved an intermolecular [2 + 2 + 2]-cross-cycloaddition using aliphatic terminal alkynes to form pyridines, with low chemoselectivity in most cases (Scheme 1c).16 Although there have been a few reports on the intermolecular [2 + 2 + 2] cyclizations of aromatic terminal alkynes with nitriles to pyridines, the reactions could not occur without the use of a metal catalyst.17 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. Most recently, photoinduced and photosensitized organic transformations have received considerable attention due to © 2017 American Chemical Society

their superiority in terms of mild reaction conditions, and they have been used as a powerful platform for the construction of target molecules.18,19 But there have been a few related to the synthesis of pyridine cores.20 Very recently, we reported a direct method for the generation of 4-aryl tetralones via a visible-light induced cyclization of styrenes with molecular oxygen.21 In order to further explore other photoinduced cycloadditions, our attempts used alkynes as the substrate for producing cyclic compounds. After comparison of the oxidative Received: February 11, 2017 Published: April 3, 2017 1958

DOI: 10.1021/acs.orglett.7b00292 Org. Lett. 2017, 19, 1958−1961

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Organic Letters

not palpably change when the reaction was performed under an N2 atmosphere (entry 9), which indicated that N2 was not 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

potential of alkenes with alkynes, a pyrylium salt with higher oxidative power could be used as photocatalyst for promoting a new reaction under visible-light irradiation.22 To our delight, a highly regioselective [2 + 2 + 2] annulation of aromatic alkynes with nitriles to form 2,3,6-trisubstituted pyridines under visiblelight irradiation using the pyrylium salt as the photoredox catalyst was developed (Scheme 1d). Although 2,4,6-triarylpyridines have been synthesized from the reaction of aryl ketones and benzylamines using eosin Y as the photoredox catalyst under visible-light irradiation,23 the preparation of the pyridine nucleus from alkynes and nitriles through organocatalytic [2 + 2+2] methodology has rarely been investigated.24 Herein, we report this pyrylium-catalyzed and photoinduced [2 + 2 + 2] cyclization of two aromatic alkynes with a nitrile to 2,3,6trisubstituted pyridines under metal-free conditions. At the outset, a solution of phenylacetylene (2a) and 2,4,6triphenylpyrylium tetrafluoroborate (TPPT) in CH3CN (1a, excess) was irradiated with blue light under various conditions, and the results are listed in Table 1. After the reaction was

Scheme 2. Scope of the Aromatic Alkynesa,b

Table 1. Optimization of the Reaction Conditionsa

a Reaction conditions: aromatic alkyne (2, 0.40 mmol), CH3CN (1a, 2.0 mL), T(p-Cl)PPT (0.06 mmol), blue LED, sealed tube, room temperature, 12 h. bIsolated yield. cReaction for 6 h.

alkynes with either an electron-rich substituent (Me, Et, Pr, Bu, and tBu) or an electron-poor substituent (F, Cl, and Br) on the 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-methylbenzene was reacted with CH3CN under the standard reaction 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 1,5hydrogen 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 1,7diphenylhepta-1,6-diyne) failed as substrates in the reaction. It should be noted that we could not observe correlative

a

Reaction conditions: phenylacetylene (2a, 0.40 mmol), CH3CN (1a, 2.0 mL), photocatalyst (0.06 mmol), sealed tube, room temperature, light irradiation for 12 h. bIsolated yield. cNR = no reaction. dUnder N2.

performed in a sealed tube at room temperature for 12 h, pyridine derivative 3aa was generated as a colorless solid in 42% yield via a [2 + 2 + 2] cycloaddition process (entry 1), and its structure was determined by NMR spectroscopy and HRMS analysis. 17a A survey of different color light sources demonstrated that the blue LED was the best choice (entries 2 and 3). No obvious effect was observed after the anion of the catalyst was changed from BF4− to CF3SO3− (entry 4 vs 1). 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 1959

DOI: 10.1021/acs.orglett.7b00292 Org. Lett. 2017, 19, 1958−1961

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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 bengal, and rhodamine B) that had low potentials18a 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

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 Scheme 3. Scope of the Nitrilesa,b

Scheme 4. Proposed Mechanism

electron-oxidation of alkyne 2a (Eox = +2.163 V) to form radical cation A in the presence of the excited state of T(pCl)PPT (E1/2 red* = +2.3 V) as the photocatalyst could be 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 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 chainpropagation electron transfer from another alkyne substrate 2a.25 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 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.

a 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 NCCH2CH2CN in 10 equiv, 2.0 mL of DCE as solvent). bIsolated yield.

of carbon chains, including butyronitrile, isobutyronitrile, valeronitrile, and isovaleronitrile, could be reacted with aromatic alkynes to produce the corresponding 2,3,6trisubstituted 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 2cyanoacetate, proceeded well in the reaction with 2a, providing the corresponding product (3ha) in 55% yield. Furthermore, the reactions of deuterated acetonitrile (CD3CN) with different aromatic alkynes afforded the cyclization products (3ia, 3if, and 3ij) with a CD3 moiety in 42−52% yields. When dicyano 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 the reaction with CH3CN under the standard reaction conditions, a mixture of pyridines was observed by 1H 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

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00292. 1960

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Lei Wang: 0000-0001-6580-7671 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (21572078, 21372095, 21402061), Young Talent Key Project of Anhui Province (gxyqZD2016411), and the Natural Science Foundation of Anhui (No. 1708085MB45) for financial support of this work.

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