Letter pubs.acs.org/OrgLett
Atom-Economic Route to Cyanoarenes and 2,2′-Dicyanobiarenes via Iron-Catalyzed Chemoselective [2 + 2 + 2] Cycloaddition Reactions of Diynes and Tetraynes with Alkynylnitriles Divya Bhatt,† Hrishikesh Chowdhury,† and Avijit Goswami* Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab 140001, India S Supporting Information *
ABSTRACT: An efficient protocol for the synthesis of cyanoarenes has been developed via an iron-catalyzed chemoselective [2 + 2 + 2] cycloaddition reaction of diynes with alkynylnitriles under mild reaction conditions with good to excellent yields. The reaction is catalyzed by the combination of FeCl2·4H2O as a metal source, 2-(2,6-diisopropylphenyl)iminomethylpyridine (dipimp) as a ligand, and Zn as a reducing agent in DME solvent. The protocol was further extended to the synthesis of 2,2′dicyanobiarene skeletons from the reaction of tetraynes with alkynylnitriles.
T
Scheme 1. Synthesis of Cyanoarene Derivatives Applying [2 + 2 + 2] Cycloaddition Reactions
he nitrile group is a prevalent moiety in a number of natural products, pharmaceuticals, dyes, and agrochemicals.1 Owing to the easy functional group transformation of nitrile moiety to amines, amides, acids, and aldehydes, this functionality is an interesting target for the synthetic community.2 However, the methods to introduce a cyano group on an aromatic/heteroaromatic ring are still limited. The transition-metal-catalyzed cyanation of aromatic halides has emerged as an attractive method to access the aromatic/ heteroaromatic nitriles.3 However, these methods involve the use of toxic reagents like KCN, CuCN, NaCN, etc. as cyano source and require harsh reaction conditions in several cases. Recently, this issue has been addressed to a certain extent by using organic precursors bearing a cyano unit4 such as acetone cyanohydrins and its analogues, alkyl nitriles, malononitrile, phenyl cyanates, benzyl thiocyanates, N-cyanobenzimidazole, nitromethane, and N-cyano-N-phenyl-p-toluenesulfonamide (NCTS). Interestingly, all of the above employed methods involve introducing a cyano group on the already available aromatic/heteroaromatic ring. Alternatively, transition-metalcatalyzed [2 + 2 + 2] cycloaddition is a well-known atomeconomical and straightforward strategy for the construction of aromatic rings5 and introduction of a functional group on the ring in a single operation. Numerous metal catalysts using metal sources like Fe, Co, Rh, Ir, Ru, Ni, Pd, and Nb have been employed for this purpose. In the context of synthesizing functionalized aryl/heteroaryl moieties, few examples have been reported for the synthesis of 2-vinylpyridines6 by the reaction of diynes with acrylonitriles (a potential bifunctional reactant containing an alkene and a nitrile group) via metal-catalyzed [2 + 2 + 2] cycloaddition reactions (Scheme 1). In addition, Hiyama et al. reported the synthesis of tricyanobenzene © 2017 American Chemical Society
derivatives via Ni-catalyzed self-cyclotrimerization of alkynylnitrile.7 These results prompted us to employ 1-cyanoalkynes for the formation of cyanoarenes in a chemoselective manner. To the best of our knowledge, no example of fused cyanoarene has been reported so far via a transition-metal-catalyzed [2 + 2 + 2] cycloaddition reaction. Herein, we report an iron-catalyzed chemoselective [2 + 2 + 2] cycloaddition reaction of α,ω-diynes with alkynylnitriles for the synthesis of fused cyanoarenes under mild reaction conditions. Initially, diyne 1a and alkynylnitrile 2a were selected as model substrates for the synthesis of fused cyanoarene 3aa via metal-catalyzed chemoselective [2 + 2 + 2] cycloaddition reaction. An array of catalysts involving Ru, Co, Received: April 22, 2017 Published: June 12, 2017 3350
DOI: 10.1021/acs.orglett.7b01217 Org. Lett. 2017, 19, 3350−3353
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
entry
catalyst (mol %)/(additive)
solvent
temp (°C)
time
yieldb (%) of 3aa/3′aa
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Cp*RuCl(COD) (5) Grubb’s II (5) CpCo(COD) (10) CpCo(CO)2 (10) [Ir(COD)Cl]2 (10)/dppe (20) [Ir(COD)Cl]2 (10)/dppf (20) (PPh3)3RhCl (10) Ni(COD)2 (10)/xantphos (10) Pd2(dba)3 (5)/PPh3 (10) CoCl2·6H2O (5)/Zn (10) CoCl2·6H2O (5)/dppe (6)/Zn (10) CoCl2·6H2O (5)/dipimp (6)/Zn (10)/(AgOTf) (10) FeI2 (10)/dppe (10/20)/Zn (20/40) FeI2 (10)/dipimp (11)/Zn (20) FeI2 (10)/dppp (10/20)/Zn (20/40) FeCl2·4H2O (5)/Zn (10) FeCl2·4H2O (5)/dipimp (6)/Zn (10) FeCl2·4H2O (5)/dipimp (6)/Zn (10) FeCl2·4H2O (5)/dipimp (6)/Zn (10)/(AgOTf) (10) FeCl2·4H2O (5)/dipimp (6)/Zn (10)
DCE DCE xylene xylene benzene benzene ethanol toluene toluene THF THF/NMP THF THF THF/ethanol THF THF/ethanol THF ethanol ethanol DME
rt 80 110 110 80 80 70 rt 110 rt rt rt rt rt rt rt rt rt rt rt
1h 2h 24 h 24 h 6h 6h 8h 2h 24 h 24 h 24 h 1h 24 h 24 h 24 h 24 h 2h 30 min 5h 20 min
58:21 49:14 44:12 41:14 48:5 54:7 47:trace 21:trace trace:trace trace:trace trace:trace 62:trace trace:trace trace:trace trace:trace trace:trace 72:trace 81:trace 21:trace 86:trace
Optimized reagents and conditions: 1 (118 mg, 0.5 mmol), 2 (76.2 mg, 0.6 mmol), FeCl2·4H2O (4.9 mg, 0.025 mmol), dipimp (7.9 mg, 0.03 mmol), Zn powder (3.2 mg, 0.05 mmol), 1,2-dimethoxyethane (DME) (2.5 mL), rt, 20 min. bIsolated yield.
a
With the optimized reaction conditions in mind, we further explored various symmetrical diynes 1 and alkynylnitriles 2 to determine the scope of substrates of the iron-catalyzed chemoselective cycloaddition reaction leading to the fused cyanoarene derivatives 3 (Scheme 2). A library of multisubstituted cyanoarene derivatives 3 were synthesized in good to excellent yields. It is worth noting that all of the cycloadditions were successfully carried out using various alkyl- and aryl-substituted alkynylnitriles as well as various carbon-, oxygen-, and nitrogen-tethered diynes, indicating the remarkable functional group compatibility of this protocol. Interestingly, tricyanoarene by self-trimerization of alkynylnitrile was not observed in any case. Compound 3cd was isolated as a pure single crystal, and the structure was confirmed by single-crystal X-ray8 analysis. Encouraged by the results, unsymmetrical diynes were employed to explore the regioselectivity for the cycloaddition reaction (Scheme 3). Four different unsymmetrical diynes 4a− d were examined with various alkynylnitriles 2 under the optimized reaction conditions, and excellent regioselectivity (except for the 4c diyne) was observed without compromising the yield of the cycloaddition products. Compound 5da was isolated as a pure single crystal, and the structure was further confirmed by single-crystal X-ray8 analysis. To judge the potential of the newly developed strategy, we concentrated our efforts on the synthesis of fused dicyanobiphenyl skeletons 7 via iron-catalyzed [2 + 2 + 2] cycloaddition reaction of tetraynes 6 with various alkynylnitriles 2 under optimized reaction conditions, and the results are summarized in Scheme 4. To our delight, 2,2′-dicyanobiarene derivatives 7 were obtained by the aforementioned cycloaddition reactions in good to excellent yields, and the other two possible
Ir, Ni, Rh, Pd, and Fe metal complexes were employed in this survey, and the results are summarized in Table 1. At the onset, RuCp*(COD)Cl was tested as a catalyst in DCE for the cycloaddition reaction, and a mixture of fused cyanobenzene (3aa) and 2-alkynylpyridine (3′aa) was obtained (Table 1, entry 1). The cycloaddition reaction was further explored using Grubb’s II, CpCo(CO)2, CpCo(COD), and [Ir(COD)Cl]2/ligand as catalysts; however, none of them could offer us an exclusive cyanoarene product (3aa) (Table 1, entries 2−6). During this survey, it was observed that Rh and Ni metal complexes were able to provide the cyanoarene compound 3aa in an exclusive chemoselective manner, although the yields were not satisfactory (Table 1, entries 7 and 8). On the other hand, Pd2(dba)3/PPh3, CoCl2·6H2O/Zn, and CoCl2·6H2O/dppe/Zn catalysts completely failed to furnish the cycloaddition adduct 3aa (Table 1, entries 9−11). Replacing dppe with dipimp ligand to the CoCl2·6H2O/ligand/ Zn system followed by addition of AgOTf led to the cycloadduct 3aa in 62% yield (Table 1, entry 12). In the process to enhance the yield of the cycloadduct, the reaction was performed using FeI2/ligand/Zn metal complexes as catalysts. Unfortunately, no cycloadduct 3aa was obtained in any case (Table 1, entries 13−15). The reaction was further carried out in the presence of a catalytic combination of FeCl2· 4H2O/dipimp/Zn in THF, and the desired cycloadduct 3aa was achieved in good yield (Table 1, entry 17). When the solvent was changed from THF to ethanol, the yield of 3aa was further improved to 81% (Table 1, entry 18). The use of the FeCl2·4H 2O/dipimp/Zn catalytic combination in DME afforded the cycloadduct 3aa in 86% yield within 20 min (Table 1, entry 20). 3351
DOI: 10.1021/acs.orglett.7b01217 Org. Lett. 2017, 19, 3350−3353
Letter
Organic Letters Scheme 2. Iron-Catalyzed Chemoselective [2 + 2 + 2] Cycloaddition Reactions of Symmetrical Diynes with Alkynylnitriles to Cyanoarenesa
Scheme 4. Iron-Catalyzed Regioselective [2 + 2 + 2] Cycloaddition Reactions for the Synthesis of 2,2′Dicyanobiarenesa
a Reagents and conditions: 6 (0.5 mmol), 2 (3 mmol), FeCl2·4H2O (4.9 mg, 0.025 mmol), dipimp (7.9 mg, 0.03 mmol), Zn powder (3.2 mg, 0.05 mmol), DME (2.5 mL), rt, 20 min.
ligands as shown in Figure 1. Due to the poor σ-donating capacity of dipimp and DME ligands, the resulting electron-
a Reagents and conditions: 1 (0.5 mmol), 2 (0.6 mmol), FeCl2·4H2O (4.9 mg, 0.025 mmol), dipimp (7.9 mg, 0.03 mmol), Zn powder (3.2 mg, 0.05 mmol), DME (2.5 mL), rt, 20 min.
Scheme 3. Regioselectivity Studies for Iron-Catalyzed [2 + 2 + 2] Cycloaddition Reaction Using Usymmetrical Diynes with Alkynylnitrilesa
Figure 1. Rationalization of the chemoselectivity of the catalyst.
deficient metal complexes A and B coordinate preferentially with the electron-rich triple bonds of alkynylnitriles. In addition, dppe-bound electron-rich metal complex C preferentially coordinates with the electron-deficient nitrile moiety. The excellent regioselectivity of the protocol may be controlled by the electronic nature of the diynes and alkynylnitriles. The relative electron density of the alkyne moieties of diynes and alkynylnitriles is shown in Figure 2. Thus, the relatively electron-rich carbon centers of metallacyclopentadienyl complexes interact with the electron-poor position of alkyne moieties of alkynylnitrile in all cases. In conclusion, we have developed an efficient, straightforward, atom-economic protocol for the chemoselective synthesis of functionalized cyanoarenes through an iron-catalyzed [2 + 2
a Reagents and conditions: 4 (0.5 mmol), 2 (0.6 mmol), FeCl2·4H2O (4.9 mg, 0.025 mmol), dipimp (7.9 mg, 0.03 mmol), Zn powder (3.2 mg, 0.05 mmol), DME (2.5 mL), rt, 20 min.
regioisomers 7′ and 7″ were not found in any case. Compound 7cb was isolated as a pure single crystal, and the structure was unequivocally confirmed by single-crystal X-ray8 analysis. In the course of rationalizing the exclusive chemoselectivity of the catalyst, it was noticed from the literature that other than cationic ruthenium complexes9 most of the metal complexes reported so far coordinate with the alkyne moieties of the alkynylnitriles. In addition, the chemoselectivity can be explained by considering the σ-donating ability of bidentate
Figure 2. Regioselectivity governed by the electronic nature of the substrates. 3352
DOI: 10.1021/acs.orglett.7b01217 Org. Lett. 2017, 19, 3350−3353
Letter
Organic Letters
(4) (a) Reeves, J. T.; Malapit, C. A.; Buono, F. G.; Sidhu, K. P.; Marsini, M. A.; Sader, C. A.; Fandrick, K. R.; Busacca, C. A.; Senanayake, C. H. J. Am. Chem. Soc. 2015, 137, 9481. (b) Motokura, K.; Matsunaga, K.; Miyaji, A.; Yamaguchi, S.; Baba, T. Tetrahedron Lett. 2014, 55, 7034. (c) Schareina, T.; Zapf, A.; Cotté, A.; Gotta, M.; Beller, M. Adv. Synth. Catal. 2011, 353, 777. (d) Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 5608. (e) Anbarasan, P.; Neumann, H.; Beller, M. Chem. - Eur. J. 2010, 16, 4725. (f) Park, E. J.; Lee, S.; Chang, S. J. Org. Chem. 2010, 75, 2760. (g) Zhang, Z.; Liebeskind, L. S. Org. Lett. 2006, 8, 4331. (5) Recent transition-metal-catalyzed [2 + 2 + 2] cycloadditions to arenes: (a) Ye, F.; Haddad, M.; Michelet, V.; Ratovelomanana Vidal, V. Org. Lett. 2016, 18, 5612. (b) Jungk, P.; Fischer, F.; Hapke, M. ACS Catal. 2016, 6, 3025. (c) Simon, C.; Amatore, M.; Aubert, C.; Petit, M. Org. Lett. 2015, 17, 844. (d) Lipschutz, M. I.; Chantarojsiri, T.; Dong, Y.; Tilley, T. D. J. Am. Chem. Soc. 2015, 137, 6366. (e) Chowdhury, H.; Chatterjee, N.; Goswami, A. Eur. J. Org. Chem. 2015, 7735. (f) Goswami, A.; Ito, T.; Okamoto, S. Adv. Synth. Catal. 2007, 349, 2368. (g) Yamamoto, Y.; Ishii, J.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 9625. (h) Chouraqui, G.; Petit, M.; Aubert, C.; Malacria, M. Org. Lett. 2004, 6, 1519. (6) (a) Kumar, P.; Prescher, S.; Louie, J. Angew. Chem., Int. Ed. 2011, 50, 10694. (b) Tanaka, K.; Suzuki, N.; Nishida, G. Eur. J. Org. Chem. 2006, 3917. (c) Onodera, G.; Shimizu, Y.; Kimura, J.; Kobayashi, J.; Ebihara, Y.; Kondo, K.; Sakata, K.; Takeuchi, R. J. Am. Chem. Soc. 2012, 134, 10515. (7) Nakao, Y.; Hirata, Y.; Tanaka, M.; Hiyama, T. Angew. Chem., Int. Ed. 2008, 47, 385. (8) CCDC 1544258 (3cd), CCDC 1550473 (5da), and CCDC 1540531 (7cb) contain the supplementary crystallographic data for this paper. (9) Cordiner, R. L.; Corcoran, D.; Yufit, D. S.; Goeta, A. E.; Howard, J. A. K.; Low, P. J. Dalton Trans. 2003, 3541.
+ 2] cycloaddition reaction of diynes with alkynylnitriles under mild reaction conditions with good to excellent yields. The developed catalyst system consists of FeCl2·4H2O/dipimp/Zn and furnishes cycloadduct within 20 min in the absence of any additive. The protocol shows remarkable chemo- and regioselectivity without compromising the yield of the cycloaddition products. This protocol also offers us as a strong synthetic tool for the construction of 2,2′-dicyanobiarenes from the reaction of tetraynes with alkynylnitriles.
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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.7b01217. Experimental procedures and detailed characterization data for the compounds; X-ray data for compound 3cd, 5da, and 7cb (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Avijit Goswami: 0000-0003-2798-1956 Author Contributions †
All authors conributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge financial support from SERB, Department of Science and Technology, New Delhi, India, and thank IIT Ropar for infrastructural facilities. D.B. and H.C. thank UGC & IIT Ropar, respectively, for their fellowships. We also acknowledge Dr. C. M. Nagaraja, Department of Chemistry, IIT Ropar, for solving the single-crystal structures presented in this work.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01217 Org. Lett. 2017, 19, 3350−3353
