α-Iminonitrile: a new cyanating agent for the palladium catalyzed C–H cyanation of arenes

Abstract

An efficient palladium-catalyzed C–H cyanation reaction of arenes using α-iminonitrile as a new cyanating reagent has been developed. With high regioselectivity and broad substrate scope, this reaction offers monocyanated products in moderate to excellent yields.

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Aryl nitriles as key structural motifs are widely present in numerous natural products, pharmaceuticals, agrochemicals and pigments.^1,2 Moreover, aryl nitriles can be easily converted into other important functionalized compounds, such as amines, tetrazoles, aldehydes, amides and other carboxy derivatives.^1,3 Therefore, many methods have been developed to introduce cyano groups into aromatic rings. The typical synthetic routes to aryl nitriles are the Sandmeyer⁴ reaction and the Rosenmund–von Braun⁵ reaction, which suffer from critical drawbacks including the stoichiometric use of toxic metal cyanides and relatively harsh reaction conditions. In addition, aryl nitriles can also be formed from aryl halides^1a,6 or arylboronic acids^6,7 with inorganic cyanide salts (such as CuCN, NaCN, KCN, Zn(CN)₂, K₄Fe(CN)₆etc.) through metal-catalyzed coupling reactions. However, the inorganic cyanide salts are highly toxic and hard to handle, and the generated metal waste generally induces an environmental issue. Recently, a few new cyano reagents were discovered to achieve aromatic cyanation reactions, such as nitromethane,⁸ tosylcyanide,⁹ acetone cyanohydrin,¹⁰ ethylcyanoacetate,¹¹ isocyanide,¹² formamide,¹³ DMF/NH₃,¹⁴ TBN (tert-butyl nitrite),¹⁵ AIBN (2,2′-azobisisobutyronitrile)¹⁶ and NCTS (N-cyano-N-phenyl-p-toluenesulfonamide)¹⁷etc.¹⁸ Still, safer and easier to handle cyano reagents are highly desired.

In recent years, the topic of C–C bond activation has been a longstanding interest due to the prevalence of C–C bonds in organic molecules.¹⁹ The search for new cyano source by C–CN bond cleavage has increasingly attracted the attention of chemists.

For example, in 1998, Cheng and co-workers²⁰ discovered that the Pd catalyzed cyanation of aryl halides using alkyl nitriles as cyano source (Scheme 1a). In this method, however, only the ortho-substituted bromoarenes showed higher reactivity. After that, Wang and Lu²¹ reported benzyl nitrile as a cyano anion surrogate under copper-catalyzed cyanation of arenes (Scheme 1b). Subsequently, an aromatic C–H bond cyanation by Cu-catalyzed acetonitrile C–CN bond cleavage was demonstrated by Shen.²² Very recently, apractical method for aryl nitrile synthesis by transnitrilation from dimethylmalononitrile to aryl Grignard or lithium reagents has been documented by Reeves (Scheme 1c).²³ Although these investigations and reactions open a new door for the search of new cyano source by C–CN bond cleavage, nevertheless, most of them involve the use of an expensive aryl halides or the specific substrates, thus, the scope of the applications of these methods is limited.

Scheme 1 Transition metal catalyzed cyanation reaction.

Transition-metal-catalyzed C–H activation as an alternative to the traditional cross-coupling reactions has evolved into a straightforward and powerful tool in organic synthesis.²⁴ Among many examples of C–H activation, the reactions of cyanation at the C2 position of 2-phenylpyridine have been extensively studied.^{17g,f,21a,22a} In continuation of our ongoing research towards the development of more efficient and selective cyanation methods,^12d,25 here we describe the aromatic C–H cyanation reaction by using α-iminonitrile as a new nitrile source.

Initially, we found that the benzonitrilic compound was formed with dissolving iodobenzene and α-iminonitrilein DMSO in the presence of 10 mol% Pd(OAc)₂ and Cu(TFA)₂ at 120 °C.²⁵ Encouraged by the result, we attempted the cyanation of aromatic C–H bonds with α-iminonitrile. We started our investigation by using 2-phenylpyridine (1a) with 1.5 equiv. of N-(tert-butyl)-benzimidoyl cyanide (2a) and 2.0 equiv. of Cu(TFA)₂ in dichloroethane (DCE) in the presence of Pd(OAc)₂ under air at 120 °C for 24 h, to our surprise the aryl nitrile 3a was found in 71% yield (Table 1, entry 1). Subsequently, solvent screening showed that tetrahydrofuran (THF) was effective apparently (Table 1, entry 2–5). Then, various additives were screened, and it was important to note that the cyanation of 1a did not take place in the absence of copper salt, which suggested the copper was necessary to the reaction (Table 1, entry 6–11). We considered that the copper cation might play an irreplaceable role in the process of C–CN bond cleavage. In addition, the absence of palladium or the use of other palladium species such Pd(TFA)₂ and Pd₂(dba)₃ did not give better results (Table 1, entry 12–14). Reducing the temperature and shorting time decreased the yield of product (Table 1, entry 15 and 16). Eventually, the optimized reaction conditions for the cyanation of C–H bond were Pd(OAc)₂ (5 mol%) as catalyst, Cu(TFA)₂ (2.0 equiv.) as additive and THF as solvent, under air at 120 °C for 24 h.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Additives	Solvent	Yield^b [%]
a Reaction conditions: all reactions were performed under air with 1a (0.5 mmol), 2 (1.5 equiv.), Pd(OAc)2 (0.05 equiv.), additive (2.0 equiv.) in 2 mL of solvent at 120 °C for 24 h in a sealed tube. b Isolated yield. c 12 h. d 100 °C.
1	Pd(OAc)2	Cu(TFA)2	DCE	71
2	Pd(OAc)2	Cu(TFA)2	Toluene	68
3	Pd(OAc)2	Cu(TFA)2	Dioxane	79
4	Pd(OAc)2	Cu(TFA)2	THF	90
5	Pd(OAc)2	Cu(TFA)2	CH3CN	37
6	Pd(OAc)2	CuCl2	THF	83
7	Pd(OAc)2	CuBr2	THF	43
8	Pd(OAc)2	Cu(OAc)2	THF	<5
9	Pd(OAc)2	—	THF	0
10	Pd(OAc)2	Ag2CO3	THF	0
11	Pd(OAc)2	PhI(OAc)2	THF	Trace
12	—	Cu(TFA)2	THF	73
13	Pd(TFA)2	Cu(TFA)2	THF	82
14	Pd2(dba)3	Cu(TFA)2	THF	78
15	Pd(OAc)2	Cu(TFA)2	THF	66^c
16	Pd(OAc)2	Cu(TFA)2	THF	60^d

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With the optimized conditions in hands, then, the substrate scope of this reaction was tested. As illustrated in Table 2, the cyanation of 2-phenylpyridine derivatives with para-, meta-, ortho-, or multisubstitutions on the aryl ring was highly efficient and showed excellent monoseclectivity. Substrates with electron-rich and -poor substitution at para-position of phenyl ring could all afford corresponding cyanated products in moderate to excellent yields, and electron-rich groups led to higher product yield in general (3e–3j). Steric hindrance has a large influence on the reaction. As the result, substrate with ortho-methyl group on the phenyl ring gave the cyanated product in 49% yield (3b). In addition, a variety of functional groups, such as halogen (3i, 3j), ketone (3k), ester (3l) and ether (3e–3h) were also compatible with present conditions, thus offering an opportunity for additional functionalizations. 2-(2-Naphthalen-2-yl)pyridine was cyanated selectively at C3 position in 87% yield (3n). 7,8-Benzo[h]quinolinewas transformed to desired product (3o) in 77% yield. Then, we examined the feasibility of this method in cyanation of heterocyclic C–H bond, such as thiophenyl, furanyl and pyrrolyl. Unfortunately, only the cyanation of pyrrolyl took place, gave the dicyanated product in 40% yield (3p). Interestingly, the monocyanated product was not observed.

Table 2 Cyanation of arene substrates^a

a Reaction conditions: 1a (0.5 mmol), 2 (1.5 equiv.), Pd(OAc)₂ (0.05 equiv.), Cu(TFA)₂ (2.0 equiv.) in 2 mL of solvent at 120 °C for 24 h in a sealed tube. Isolated yield. b 36 h. c 30 h.

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Thereafter, we exploited the use of other directing groups (DGs) for this reaction. As illustrated in Table 3, with pyrimidine (5a) and pyrazole (5e) as DG, the cyanated product was formed in good yield. In addition, substrates with both electron-donating and -withdrawing group on the para position of phenyl ring were also tolerable under the reaction conditions, gave the desired products in moderate to acceptable yield (5c–d, 5g–h).

Table 3 Cyanation of other DGs substrates^a

a Reaction conditions: 4a (0.5 mmol), 2 (1.5 equiv.), Pd(OAc)₂ (0.05 equiv.), Cu(TFA)₂ (2.0 eq.) in 2 mL of solvent at 120 °C for 24 h. Values in parentheses are the isolated yields based on the reacted substrates. b 48 h.

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To further demonstrate the capability of the cyanation reaction, we tested several α-iminonitriles with 1a under the optimized conditions, as depicted in Table 4. While cyanation with α-iminonitrile substituted with electron-donating (2b) and -withdrawing groups (2c), the yield of 3a was moderate. Using N-phenyl (2d), -cyclopropyl (2e) substituted α-iminonitrile instead of 2a, the yield was decreased apparently. In addition, α,β-unsaturated iminonitrile (2f) was compatible with the method, giving 3a in 53% yield. A nice result about this reaction was that the C–CN bond cleavage also happened when aliphatic iminonitrile was treated with 1a under the same condition, gratifyingly, the desired product 3a was obtained in 75% yield (2g). The result indicated that iminonitriles with arene and alkyl substitution were all feasible CN sources for this cyanation reaction, and the further studies are underway in our laboratory.

Table 4 Cyanation of other iminonitriles^a

Entry	2	R^1	R^2	3a yield^b [%]
a Reaction conditions: 1a (0.5 mmol), 2 (1.5 equiv.), Pd(OAc)2 (0.05 equiv.), Cu(TFA)2 (2.0 eq.) in 2 mL of solvent at 120 °C for 24 h. b Isolated yield.
1	2a	C6H5	t-Bu	90
2	2b	4-MeOC6H4	t-Bu	59
3	2c	4-FC6H4	t-Bu	66
4	2d	C6H5	C6H5	28
5	2e	C6H5	(CH2)2CH	21
6	2f	PhCH=CH	Ph(CH2)2	53
7	2g	(CH3)2CH	Ph(CH2)2	75

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Next, to comprehend the mechanistic of the cyanation reaction, we performed some preliminary experiments as depicted in Scheme 2. Under standard conditions, substrate 1a was found to undergo a notable H/D exchange in the presence of CD₃OD (Scheme 2a), which showed that the C–H activation step would be reversible. In addition, the experiment of intermolecular kinetic isotope effect (KIE) in two parallel reactions (k_H/k_D = 4.8) and competitive reaction (k_H/k_D = 3.5) indicates that the C–H bond cleavage may be the rate-determining step (Scheme 2b). Subsequently, the experiment of intramolecular competition reaction (k_H/k_D = 2.0) supported the information above (Scheme 2c).

Scheme 2 Preliminary mechanistic experiments.

Based on the basis of literature,^14c,22a a plausible mechanism for the cyanation reaction is depicted in Scheme 3. Firstly, 2a undergoes a copper-catalyzed oxidation to generate intermediate 6, followed by hydrolysis to form the copper cyanide species 7. Then, the complex 7 participates in the palladium-catalyzed-cyanation cycle. The cycle is initiated with oxidative addition of 1a under Pd catalyst to form the palladium complex A. Subsequently, intermediate A reacts with copper cyanide species 7 to afford complex B. Finally, reductive elimination of complex B gives the cyanated product 3a and Pd⁰, and the Pd⁰ species is oxidized by Cu^II to regenerate the Pd^II species, which may be the resting state of the catalyst. In the absence of palladium, the copper cyanide species 7 reacts with 1a to give intermediate C,^8,16 which is subsequently oxidized to the intermediate D by the copper salts. Following reductive elimination, the product 3a is produced and the Cu^II species is regenerated to complete the copper catalytic cycle. In this case, the bivalent copper salt is used as catalyst and oxidant also.

Scheme 3 Proposed mechanism.

In summary, we have discovered a simple and efficient palladium-catalyzed cyanation of unactivated C–H bond by using α-iminonitrile as a new cyano reagent. This approach provides an alternative route for the synthesis of aryl nitriles with high regioselectivity in good to excellent yields. In addition, the optimized catalytic system tolerated various directing groups.

Acknowledgements

This work was supported by the PAPD (A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions).

Notes and references

1. (a) P. Anbarasan, T. Schareina and M. Beller, Chem. Soc. Rev., 2011, 40, 5049; (b) J. S. Miller and J. L. Manson, Acc. Chem. Res., 2001, 34, 563; (c) C. Torborg and M. Beller, Adv. Synth. Catal., 2009, 351, 3027.
2. (a) A. Kleemann, J. Engel, B. Kutscher and D. Reichert, Pharmaceutical Substances: Syntheses, Patents, Applications, Georg Thieme Verlag, Stuttgart, 4th edn, 2001, pp. 241–242; (b) E. De Clercq, Expert Opin. Emerging Drugs, 2005, 10, 241.
3. (a) R. C. Larock, Comprehensive Organic Transformations, Wiley-VCH, Weinheim, 2nd edn, 1999; (b) M. Chaitanya, D. Yadagiri and P. Anbarasan, Org. Lett., 2013, 15, 4960.
4. (a) T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1884, 17, 1633; (b) C. Galli, Chem. Rev., 1988, 88, 765.
5. (a) K. W. Rosenmund and E. Struck, Ber. Dtsch. Chem. Ges., 1919, 2, 1749; (b) J. von Braun and G. Manz, Justus Liebigs Ann. Chem., 1931, 488, 111.
6. J. Kim, H. J. Kim and S. Chang, Angew. Chem., Int. Ed., 2012, 51, 11948.
7. (a) Z. Zhang and L. S. Liebeskind, Org. Lett., 2006, 8, 4331; (b) P. Anbarasan, H. Neumann and M. Beller, Angew. Chem., 2011, 123, 539 ( Angew. Chem., Int. Ed. , 2011 , 50 , 519 ).
8. X. Chen, X.-S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006, 128, 6790.
9. S. Kamijo, T. Oshikawa and M. Inoue, Org. Lett., 2011, 13, 5928.
10. (a) S. Verma, S. L. Jain and B. Sain, Catal. Lett., 2011, 141, 882; (b) M. Sundermeier, A. Zapf and M. Beller, Angew. Chem., 2003, 115, 1700 ( Angew. Chem., Int. Ed. , 2003 , 42 , 1661 ); (c) T. Schareina, A. Zapf, A. Cotté, M. Gotta and M. Beller, Adv. Synth. Catal., 2011, 353, 777.
11. S. Zheng, C. Yu and Z. Shen, Org. Lett., 2012, 14, 3644.
12. (a) S. Xu, X. Huang, X. Hong and B. Xu, Org. Lett., 2012, 14, 4614; (b) J. Peng, J. Zhao, Z. Hu, D. Liang, J. Huang and Q. Zhu, Org. Lett., 2012, 14, 4966; (c) X. Hong, H. Wang, G. Qian, Q. Tan and B. Xu, J. Org. Chem., 2014, 79, 3228; (d) X. Jiang, J.-M. Wang, Y. Zhang, Z. Chen, Y.-M. Zhu and S.-J. Ji, Tetrahedron, 2015, 71, 4883.
13. (a) D. N. Sawant, Y. S. Wagh, P. J. Tambade, K. D. Bhatte and B. M. Bhanage, Adv. Synth. Catal., 2011, 353, 781; (b) A. B. Khemnar, D. N. Sawant and B. M. Bhanage, Tetrahedron Lett., 2013, 54, 2682; (c) K. Hosoi, K. Nozaki and T. Hiyama, Org. Lett., 2002, 4, 2849.
14. (a) J. Kim and S. Chang, J. Am. Chem. Soc., 2010, 132, 10272; (b) B. Liu, J. Wang, B. Zhang, Y. Sun, L. Wang, J. Chen and J. Cheng, Chem. Commun., 2014, 50, 2315; (c) X. Jia, D. Yang, S. Zhang and J. Cheng, Org. Lett., 2009, 11, 4716; (d) S. Ding and N. Jiao, J. Am. Chem. Soc., 2011, 133, 12374; (e) J. Kim, J. Choi, K. Shin and S. Chang, J. Am. Chem. Soc., 2012, 134, 2528; (f) A. B. Pawara and S. Chang, Chem. Commun., 2014, 448.
15. (a) Z. Shu, Y. Ye, Y. Deng, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2013, 52, 10573; (b) D. Tsuchiya, Y. Kawagoe, K. Moriyama and H. Togo, Org. Lett., 2013, 15, 4194.
16. H. Xu, P.-T. Liu, Y.-H. Li and F.-S. Han, Org. Lett., 2013, 15, 3354.
17. (a) T.-J. Gong, B. Xiao, W.-M. Cheng, W. Su, J. Xu, Z.-J. Liu, L. Liu and Y. Fu, J. Am. Chem. Soc., 2013, 135, 10630; (b) M. Chaitanya, D. Yadagiri and P. Anbarasan, Org. Lett., 2013, 15, 4960; (c) Y. Yang and S. L. Buchwald, Angew. Chem., Int. Ed., 2014, 53, 8677; (d) M. Chaitanya and P. Anbarasan, Org. Lett., 2015, 17, 3766; (e) W. Liu and L. Ackermann, Chem. Commun., 2014, 1878; (f) J. Li and L. Ackermann, Angew. Chem., 2015, 127, 3906 ( Angew. Chem. Int. Ed. , 2015 , 54 , 3635 ); (g) D.-G. Yu, T. Gensch, F. de Azambuja, S. Vásquez-Céspedes and F. Glorius, J. Am. Chem. Soc., 2014, 136, 17722; (h) Y. Yang and S. L. Buchwald, Angew. Chem., Int. Ed., 2014, 53, 8677.
18. (a) A. B. Pawarand and S. Chang, Org. Lett., 2015, 17, 660; (b) J. Liu, H.-X. Zheng, C.-Z. Yao, B.-F. Sun and Y.-B. Kang, J. Am. Chem. Soc., 2016, 138, 3294; (c) J.-J. Ge, C.-Z. Yao, M.-M. Wang, H.-X. Zheng, Y.-B. Kangand and Y.-D. Li, Org. Lett., 2016, 18, 228; (d) Q. Wu, Y. Luo, A. Leiand and J. You, J. Am. Chem. Soc., 2016, 138, 2885; (e) S.-Y. Zheng, C.-H. Yuand and Z.-W. Shen, Org. Lett., 2012, 14, 3644.
19. (a) Y. J. Park, J.-W. Park and C.-H. Jun, Acc. Chem. Res., 2008, 41, 222; (b) C.-H. Jun, Chem. Soc. Rev., 2004, 33, 610.
20. F.-H. Luo, C.-I. Chu and C.-H. Cheng, Organometallics, 1998, 17, 1025.
21. (a) J. Jin, Q. Wen, P. Lu and Y. Wang, Chem. Commun., 2012, 48, 9933; (b) Q. Wen, J. Jin, Y. Mei, P. Lu and Y. Wang, Eur. J. Org. Chem., 2013, 2013, 4032.
22. (a) X.-Z. Kou, M.-D. Zhao, X.-X. Qiao, Y.-M. Zhu, X.-F. Tong and Z.-M. Shen, Chem.–Eur. J., 2013, 19, 16880; (b) Y.-M. Zhu, M.-D. Zhao, W.-K. Lu, L.-Y. Li and Z.-M. Shen, Org. Lett., 2015, 17, 2602.
23. J. T. Reeves, C. A. Malapit, F. G. Buono, K. P. Sidhu, M. A. Marsini, C. A. Sader, K. R. Fandrick, C. A. Busacca and C. H. Senanayake, J. Am. Chem. Soc., 2015, 137, 9481.
24. Foe some reviews on C–H activation, see: (a) S. A. Girard, T. Knauber and C.-J. Li, Angew. Chem., Int. Ed., 2014, 53, 74 ( Angew. Chem. , 2014 , 126 , 76 ); (b) H. Kim and S. Chang, ACS. Catal., 2016, 6, 2341; (c) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5, 369; (d) S. Tani, T. N. Uehara, J. Yamaguchi and K. Itami, Chem. Sci., 2014, 5, 123.
25. Z.-B. Chen, Y. Zhang, Q. Yuan, F.-L. Zhang, Y.-M. Zhu and J.-K. Shen, J. Org. Chem., 2016, 81, 1610.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra14512d

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