Palladium-Catalyzed Synthesis of Aryl Nitriles: Using α-Imino­nitrile as Cyano Source for Aryl Halide Cyanations

Abstract

An efficient and ligand-free palladium-catalyzed exchange reaction to synthesize aryl nitriles by using α-iminonitrile as a starting reagent has been developed. This methodology provides an optional method for the synthesis of aryl nitriles with moderate to good yields. At the same time, this approach is adaptable for many substrates.

Aryl nitrile is a basic structure of natural product and synthetic organic compounds, and it can be found widely in dyes, herbicides, agrochemicals, and electronic materials.[1] In addition, the cyano group of aryl nitriles can be transformed into other functionalities to build more complex and useful compounds, such as amines, amidines, tetrazoles, aldehydes, amides, or other carboxy derivatives,[2] which has attracted much attention. Traditional methods to generate aryl nitriles are the diazotization of anilines followed by Sandmeyer reaction[3] and the Rosenmund–Vonbraun reaction.[4] However, the reaction requires stoichiometric amounts of CuCN and must be conducted under harsh conditions. Other cyanation reactions have been developed by using various cyano sources. The majority of new procedures commonly use metal- or metalloid-bound cyano sources, including KCN,[5] NaCN,[6] Zn(CN)₂,[7] TMSCN,[8] or K₄[Fe(CN)₆],[9] which are coupled with aryl halides (Scheme [1a]). Although the series of protocols were widely utilized, they suffered from significant drawbacks: (a) High cyanide–metal affinity tends to decrease the activity of catalysts; (b) Careful attention should be paid to protect from cyanide hazard; (c) Environmental issues may be caused by stoichiometric amounts of waste copper; (d) Compatibility in various cyanation systems will be limited by the low solubility of inorganic cyano sources in organic solvents. Therefore, a series of nonmetallic cyano sources have been screened. In 1998, Cheng and co-workers developed a method involving Ni- or Pd- catalyzed cyanation of aryl halides with alkyl nitriles.[10] However, the method require high temperature and phosphate ligand. Subsequently, Beller and co-workers demonstrated that they could maintain the activity of catalysts by using cyanohydrin[11] as cyano source; cyanohydrin can be gradually injected into the reaction and prevent the overdose of cyano group (Scheme [1b]). Since then, benzyl cyanide,[12] malononitrile,[13] thiocyanates,[14] phenyl cyanate,[15] and N-cyano-N-phenyl-p-toluenesulfonamide (NCTS)[16] were reported as organic cyano sources (Scheme [1c]). However, these methods still require relatively harsh conditions, expensive ligand or sequential reaction. Based on our previous work, we creatively chose α-iminonitrile as a cyano source and discovered a ligand-free and relatively mild reaction system that can be used to cyanate aryl halides.

In an initial study, we found that 4-methoxy iodobenzene could be converted into 4-methoxy-benzonitrile in 74% isolated yield when the trial was conducted between 1-iodo-4-methoxy-benzene and α-iminonitrile with Pd(OAc)₂ and Cu(TFA)₂ in 2 mL DMSO under air at 120 °C (Table [1], entry 1). Inspired by this result, we conducted further research to optimize reaction conditions by using 4-methoxy iodobenzene as substrate (entries 1–11). Initially, we did not use Pd(OAc)₂ and just added 2.0 equiv Cu(TFA)₂ into the reaction. To our delight, 4-methoxybenzonitrile could also be isolated in 70% yield (entry 2). Based on this result, the solvents were screened, and it was shown that cyanation could be achieved by using either DMF or DMSO (entries 2 and 3). When DMF was used as solvent, the isolated yield increased slightly. The use of other solvents only gave trace amounts of the desired product. Secondly, we screened Cu sources, such as Cu(TFA)₂, CuCl₂, CuBr₂, and Cu(OAc)₂ (entries 3, 8, 9, and 10). The nature of the Cu source had a significant effect on the reaction. Cu(TFA)₂ afforded better cyanation, with 79% isolated yield. Gradual decrease in the amount of Cu led to a decrease in the yield (entry 6). Cyanation did not take place without Cu salt (entry 7).

The reaction system was not suitable for other substrates, especially when 4-iodobiphenyl was used as substrate significant amounts of starting material remained (Table [1], entry 11). We realized that the use of Cu salt alone did not achieve effective reaction. To solve the problem, 1.0 equiv K₂CO₃ was added into the reaction (entries 12–15). The amount of starting material was monitored, and only a trace amount of 4-iodobiphenyl was detected by TLC. However, when the substrate scope of the reaction was tested, we found the reaction conditions were not suitable for some substrates, and starting materials remained. Nevertheless, 4-iodo-biphenyl (entry 12), 1-iodo-4-nitrobenzene (entry 13), N-(4-iodophenyl)acetamide (entry 14), and iodo-4-methoxybenzene (entry 15) participated in the reaction and the cyanate products were obtained in moderate to good yields.

Table 1 Optimization of the Conditions^a

Entry	Substrate	Catalyst	Additive	Solvent	Yield (%)b	Recovery (%)
1	1a	Pd(OAc)2 f	Cu(TFA)2	DMSO	74	0
2	1a	–	Cu(TFA)2	DMSO	70	0
3	1a	–	Cu(TFA)2	DMF	79	0
4	1a	–	Cu(TFA)2	THF	trace	>95
5	1a	–	Cu(TFA)2	dioxane	trace	>95
6	1a	–	Cu(TFA)2h	DMF	65	0
7	1a	Pd(OAc)2 f	–	DMF	–	>95
8	1a	–	CuCl2	DMF	30	0
9	1a	–	CuBr2	DMF	29	0
10	1a	–	Cu(OAc)2	DMF	53	0
11	1i	–	Cu(TFA)2	DMF	–	43
12	1i	–	Cu(TFA)2, K2CO3	DMF	69	trace
13	1f	–	Cu(TFA)2, K2CO3	DMF	50	0
14	1c	–	Cu(TFA)2, K2CO3	DMF	56	0
15	1a	–	Cu(TFA)2, K2CO3	DMF	80	0
16	1i	Pd(OAc)2 g	Cu(TFA)2, K2CO3	DMF	–	25
17	1i	Pd(OAc)2	Cu(TFA)2, K2CO3	DMF	–	20
18	1i	Pd(OAc)2	Cu(TFA)2	DMF	77	0
19	1i	Pd(OAc)2 g	Cu(TFA)2	DMF	–	8
20	1i	Pd(Cl)2	Cu(TFA)2	DMF	70	0
21	1i	Pd(OAc)2	Cu(TFA)2	DMF	69c	0
22	1i	Pd(OAc)2	Cu(TFA)2	DMF	65d	0
23	1a	Pd(OAc)2	Cu(TFA)2	DMF	tracee	>95

^a Reaction conditions: All reactions were performed with α-iminonitrile (0.6 mmol), haloarene (0.5 mmol), Pd cat. (0.1 mmol), Cu source (1 mmol), DMF (2 mL), 120 °C (oil bath), under air for 24 h.

^b Isolated yield. 1a = Iodo-4-methoxybenzene; 1i = 4-iodo-biphenyl; 1f = 1-iodo-4-nitrobenzene. 1c = N-(4-iodophenyl)acetamide.

^c 110 °C.

^d Reaction conducted for 18 h.

^e The reaction was performed without α-iminonitrile.

^f Pd(OAc)₂ = 0.025 mmol

^g Pd(OAc)₂ = 0.05 mmol.

^h Cu(TFA)₂ = 0.5 mmol.

Finally, Pd salt was added as catalyst and 4-iodo-biphenyl was used as substrate to optimize reaction conditions (Table [1], entries 16–22). Initially, 0.1 equiv Pd(OAc)₂ and 1.0 equiv K₂CO₃ were added to the reaction, and 25% 4-iodo-biphenyl were recovered (entry 16). When the amount of Pd salt was increased to 0.2 equiv, the recovered yield of 4-iodo-biphenyl decreased to 20% (entry 17); the residual starting material disappeared when there was no K₂CO₃ in the reaction (entry 18). Subsequent trials were conducted with 0.1 equiv Pd(OAc)₂ and no K₂CO₃, under which conditions, 8% 4-iodo-biphenyl was recovered (entry 19). PdCl₂ also can take part in the reaction and the cyanate product was obtained in slightly lower yield (entry 20).When the temperature of the reaction was reduced and the reaction time was shortened, the reaction afforded lower yield of the cyanation product (Table [1], entries 21 and 22). Interestingly, we found trace amounts of cyanate even when the reaction was performed without α-iminonitrile. Thus it may be that the DMF can also be the source of cyanide.[19] Finally, the optimized reaction conditions for cyanation of aryl halide were Pd(OAc)₂ (0.2 equiv.) as catalyst, Cu(TFA)₂ (2.0 equiv.) as oxidant and DMF as solvent, under air at 120 °C for 24 h.

With the optimal reaction conditions established, we tested substrate scope. In general, substrates with electron-donating groups (-OCH₃, -OH, -NHCOCH₃) (Table [2], entries 1–3) gave higher isolated yield compared with those with electron-withdrawing groups (-Cl, -COCH₃, -NO₂) (entries 4–6). 1-Iodo-4-methoxy-benzene give the product in 84% yield (entry 1). N-(4-Iodophenyl)acetamide could be converted into the desired cyanated product in 70% yield (entry 3). We then changed the electron-donating groups to electron-withdrawing groups. We found 1-chloro-4-iodo-benzene gave the cyanate product in 51% yield (entry 4) whereas 1-fluoro-4-iodobenzene was not converted into the 4-fluorobenzonitrile. 1-(4-Iodophenyl)ethanone (entry 5) gave the desired cyanate product in 58% yield. In addition, aryl bromides could also be cyanated under the established conditions; 9-bromo-anthracene and 2-bromo-naphthalene were converted into the product in 60% and 26% yield, respectively (entries 7 and 8). Furthermore, substrates that have a large conjugate ring in the ortho-position showed excellent compatibility with the protocol; thus, 2-iodobiphenyl and 1-iodonaphthalene gave the product in 93% and 95%, respectively (entries 10 and 11). To our surprise, substrates with other groups in the ortho-position (1-iodo-2-methoxybenzene and 1-iodo-2-methylbenzene) were not compatible with the protocol. 5-Iodo-benzo­[b]thiophene could be cyanated with α-iminonitrile in 67% (entry 15). Moreover, (2-bromovinyl)benzene furnished the product in 62% yield (entry 16).

To explain the reaction, we propose a possible mechanism in Scheme [2]. Firstly, the covalent bond between the cyano group and the imine of α-iminonitrile was cleaved by copper to afford intermediate 1; copper was an oxidant in this process. Then, intermediate 1 was hydrolyzed by water to form copper cyanide species 3 together with side product 2. Species 3 could join in both palladium-catalyzed-cyanation cycle and copper-catalyzed-cyanation cycle to generate cyanide product 7. On one hand, under Pd catalysis, substrate 9 gave palladium complex 5. Palladium complex 5 reacted with species 3 to afford complex 4. Subsequently, complex 4 gave cyanate product 7 and Pd⁰; Pd⁰ was oxidized by Cu^II and regenerated the Pd^II species. Then, Pd^II species could participate the reaction again. On the other hand, in the absence of Pd^II, copper cyanide complex 3 reacted with intermediate 8 to generate complex 6, this is then divided into product 7 and complex 10. For some substrates copper acted as both oxidant and catalyst.

Table 2 α-Iminonitrile used as Cyano Source to Cyanate Haloarenes^a

Entry	Substrate 1	1	Cyanate 2	2	Yield (%)b
1		1a		2a	84
2		1b		2b	72
3		1c		2c	70
4		1d		2d	51
5		1e		2e	58
6		1f		2f	54
7		1g		2g	60
8		1h		2h	26
9		1i		2i	77
10		1j		2j	93
11		1k		2k	95
12		1l		2l	76
13		1m		2m	12
14		1n		2n	58
15		1o		2o	67
16		1p		2p	62

^a Reaction conditions: All reactions were performed with α-iminonitrile (0.6 mmol), haloarene (0.5 mmol), Pd(OAc)₂ (0.1 mmol), Cu(TFA)₂ (1 mmol), DMF (2 mL), 120 °C (oil bath), under air for 24 h.

^b Isolated yield

In conclusion, we have discovered an effective, ligand-free way to synthesize aryl nitriles with moderate to good yield by using α-iminonitrile as cyano source.[20] [21] We hope this method will provide an further option for the synthesis of aryl nitriles.

• References and Notes

• 1a Kleemann A. Engel J. Kutscher B. Reichert D. Pharmaceutical Substance: Synthesis Patents, Applications . 4th ed. Georg Thieme; Stuttgart: 2001
  Search in Google Scholar
• 1b Miller JS. Manson JL. Acc. Chem. Res. 2001; 34: 563
  CrossrefPubMedSearch in Google Scholar
• 1c Fleming FF. Wang Q. Chem. Rev. 2003; 103: 2035
  Search in Google Scholar
• 2a Rappoport Z. Chemistry of the Cyano Group . Wiley; London: 1970
  Search in Google Scholar
• 2b Larock RC. Comprehensive Organic Transformations: A Guide to Functional Group Preparations. VCH; New York: 1989
  Search in Google Scholar
• 3a Sandmeyer T. Ber. Dtsch. Chem. Ges. 1884; 17: 1633
  CrossrefSearch in Google Scholar
• 3b Galli C. Chem. Rev. 1988; 88: 765
  CrossrefSearch in Google Scholar
• 4a Rosenmund KW. Struck E. Ber. Dtsch. Chem. Ges. 1919; 2: 1749
  Search in Google Scholar
• 4b Lindley J. Tetrahedron 1984; 40: 1433
  CrossrefSearch in Google Scholar
• 5a Sakakibara Y. Okuda F. Shimobayashi A. Kirino K. Sakai M. Uchino N. Takagi K. Bull. Chem. Soc. Jpn. 1988; 61: 1985
  CrossrefSearch in Google Scholar
• 5b Anderson BA. Bell EC. Ginah FO. Harn NK. Pagh LM.. Wepsiec JP. J. Org. Chem. 1998; 63: 8224
  CrossrefSearch in Google Scholar
• 5c Yang C. Williams JM. Org. Lett. 2004; 6: 2837
  CrossrefPubMedSearch in Google Scholar
• 5d Cristau H.-J. Ouali A. Spindler J.-F. Taillefer M. Chem. Eur. J. 2005; 11: 2483
  CrossrefPubMedSearch in Google Scholar
• 6a Okano T. Iwahara M. Kiji J. Synlett 1998; 243
  Thieme Connect
• 6b Zanon J. Klapars A. Buchwald SL. J. Am. Chem. Soc. 2003; 125: 2890
  CrossrefPubMedSearch in Google Scholar
• 7a Tschaen DM. Desmond R. King AO. Fortin MC. Pipik B. King S. Verhoeven TR. Synth. Commun. 1994; 24: 887
  CrossrefSearch in Google Scholar
• 7b Maligres PE. Waters MS. Fleitz F. Askin D. Tetrahedron Lett. 1999; 40: 8193
  CrossrefSearch in Google Scholar
• 7c Alterman M. Hallberg A. J. Org. Chem. 2000; 65: 7984
  CrossrefPubMedSearch in Google Scholar
• 7d Chidambaram R. Tetrahedron Lett. 2004; 45: 1441
  CrossrefSearch in Google Scholar
• 7e Jensen RS. Gajare AS. Toyota K. Yoshifuji M. Ozawa F. Tetrahedron Lett. 2005; 46: 8645
  CrossrefSearch in Google Scholar
• 7f Buono FG. Chidambaram R. Mueller RH. Waltermire RE. Org. Lett. 2008; 10: 5325
  CrossrefPubMedSearch in Google Scholar
• 7g Martin MT. Liu B. Cooley BE. Jr. Eaddy JF. Tetrahedron Lett. 2007; 48: 2555
  CrossrefSearch in Google Scholar
• 8a Chatani N. Hanafusa T. J. Org. Chem. 1986; 51: 4714
  CrossrefSearch in Google Scholar
• 8b Sundermeier M. Mutyala S. Zapf A. Spannenberg A. Beller M. J. Organomet. Chem. 2003; 684: 50
  CrossrefSearch in Google Scholar
• 9a Schareina T. Zapf A. Beller M. Chem. Commun. 2004; 1388
  PubMed
• 9b Weissman SA. Zewge D. Chen C. J. Org. Chem. 2005; 70: 1508
  CrossrefPubMedSearch in Google Scholar
• 9c Schareina T. Zapf A. Beller M. Tetrahedron Lett. 2005; 46: 2585
  CrossrefSearch in Google Scholar
• 9d Grossman O. Gelman D. Org. Lett. 2006; 8: 1189
  CrossrefPubMedSearch in Google Scholar
• 9e Schareina T. Zapf A. Mägerlein W. Müller N. Beller M. Tetrahedron Lett. 2007; 48: 1087
  CrossrefSearch in Google Scholar
• 10 Luo F.-H. Chu C.-I. Cheng C.-H. Organometallics 1998; 17: 1025
  CrossrefSearch in Google Scholar
• 11 Stewart TD. Fontana BJ. J. Am. Chem. Soc. 1940; 62: 3281
  CrossrefSearch in Google Scholar
• 12 Wen Q. Jin J. Hu B. Lu P. Wang Y. RSC Advances 2012; 2: 6167
  CrossrefSearch in Google Scholar
• 13 Jiang Z. Huang Q. Chen S. Long L. Zhou X. Adv. Synth. Catal. 2012; 354: 589
  CrossrefSearch in Google Scholar
• 14 Zhang Z. Liebeskind LS. Org. Lett. 2006; 8: 4331
  CrossrefPubMedSearch in Google Scholar
• 15 Sato N. Yue Q. Tetrahedron 2003; 59: 5831
  CrossrefSearch in Google Scholar
• 16 Anbarasan P. Neumann H. Beller M. Angew. Chem. Int. Ed. 2011; 50: 519 ; Angew. Chem.; 2011, 123, 539
  CrossrefPubMedSearch in Google Scholar
• 17 Kim J. Kim HJ. Chang S. Angew. Chem. Int. Ed. 2012; 51: 11949
  Search in Google Scholar
• 18 Wen QD. Lu P. Wang YG. Tetrahedron Lett. 2014; 55: 1271
  CrossrefSearch in Google Scholar
• 19a Zhang LP. Lu P. Wang YG. Chem. Commun. 2015; 2840
  PubMed
• 19b Zhang LP. Lu P. Wang YG. Org. Biomol. Chem. 2015; 13: 8322
  CrossrefPubMedSearch in Google Scholar
• 20 General Procedure for the Synthesis of α-Iminonitrile: t-Butyl isocyanide (1.5 mmol), iodobenzene (0.5 mmol), PdCl₂ (0.05 mmol), PCy₃ (0.1 mmol), Cs₂CO₃ (1.0 mmol), and 4 Å MS (100 mg) were added into a 15 mL sealed tube equipped with a magnetic stirring bar and stirred in DMF (2 mL) under argon at 135 °C for 18 h. After completion of the reaction as detected by TLC, it was poured into water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried (Na₂SO₄) and evaporated. The residue was purified on a silica gel column using petroleum ether/EtOAc as the eluent to give the pure target product. N-(tert-Butyl)benzimidoyl Cyanide: Yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.97 (m, 2 H), 7.52–7.40 (m, 3 H), 1.53 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 136.8 (s), 131.8 (s), 128.8 (s), 127.3 (s), 111.8 (s), 58.5 (s), 29.5 (s). HRMS (CI): m/z [M + H]⁺ calcd for C₁₂H₁₄N₂: 186.1157; found: 186.1154.
• 21 General Procedure for the Synthesis of the Cyanate Product: Aryl halide (0.5 mmol), α-iminonitrile (0.6 mmol), Cu(TFA)₂ (1.0 mmol), Pd(OAc)₂ (0.1 mmol) and DMF (2 mL)were added to a 15 mL sealed tube containing a magnetic stirring bar, and the mixture was stirred under air at 120 °C for 24 h (the progress of the reaction was monitored by TLC). The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was dried with Na₂SO₄, evaporated, and purified by by silica gel column chromatography. 4-Methoxy-benzonitrile (2a): See ref 19. White solid; mp 59–61 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.55 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 3.83 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 162.8 (s), 133.9 (s), 119.2 (s), 114.8 (s), 103.9 (s), 77.5 (s), 77.2 (s), 76.8 (s), 55.5 (s).

• References and Notes

• 1a Kleemann A. Engel J. Kutscher B. Reichert D. Pharmaceutical Substance: Synthesis Patents, Applications . 4th ed. Georg Thieme; Stuttgart: 2001
  Search in Google Scholar
• 1b Miller JS. Manson JL. Acc. Chem. Res. 2001; 34: 563
  CrossrefPubMedSearch in Google Scholar
• 1c Fleming FF. Wang Q. Chem. Rev. 2003; 103: 2035
  Search in Google Scholar
• 2a Rappoport Z. Chemistry of the Cyano Group . Wiley; London: 1970
  Search in Google Scholar
• 2b Larock RC. Comprehensive Organic Transformations: A Guide to Functional Group Preparations. VCH; New York: 1989
  Search in Google Scholar
• 3a Sandmeyer T. Ber. Dtsch. Chem. Ges. 1884; 17: 1633
  CrossrefSearch in Google Scholar
• 3b Galli C. Chem. Rev. 1988; 88: 765
  CrossrefSearch in Google Scholar
• 4a Rosenmund KW. Struck E. Ber. Dtsch. Chem. Ges. 1919; 2: 1749
  Search in Google Scholar
• 4b Lindley J. Tetrahedron 1984; 40: 1433
  CrossrefSearch in Google Scholar
• 5a Sakakibara Y. Okuda F. Shimobayashi A. Kirino K. Sakai M. Uchino N. Takagi K. Bull. Chem. Soc. Jpn. 1988; 61: 1985
  CrossrefSearch in Google Scholar
• 5b Anderson BA. Bell EC. Ginah FO. Harn NK. Pagh LM.. Wepsiec JP. J. Org. Chem. 1998; 63: 8224
  CrossrefSearch in Google Scholar
• 5c Yang C. Williams JM. Org. Lett. 2004; 6: 2837
  CrossrefPubMedSearch in Google Scholar
• 5d Cristau H.-J. Ouali A. Spindler J.-F. Taillefer M. Chem. Eur. J. 2005; 11: 2483
  CrossrefPubMedSearch in Google Scholar
• 6a Okano T. Iwahara M. Kiji J. Synlett 1998; 243
  Thieme Connect
• 6b Zanon J. Klapars A. Buchwald SL. J. Am. Chem. Soc. 2003; 125: 2890
  CrossrefPubMedSearch in Google Scholar
• 7a Tschaen DM. Desmond R. King AO. Fortin MC. Pipik B. King S. Verhoeven TR. Synth. Commun. 1994; 24: 887
  CrossrefSearch in Google Scholar
• 7b Maligres PE. Waters MS. Fleitz F. Askin D. Tetrahedron Lett. 1999; 40: 8193
  CrossrefSearch in Google Scholar
• 7c Alterman M. Hallberg A. J. Org. Chem. 2000; 65: 7984
  CrossrefPubMedSearch in Google Scholar
• 7d Chidambaram R. Tetrahedron Lett. 2004; 45: 1441
  CrossrefSearch in Google Scholar
• 7e Jensen RS. Gajare AS. Toyota K. Yoshifuji M. Ozawa F. Tetrahedron Lett. 2005; 46: 8645
  CrossrefSearch in Google Scholar
• 7f Buono FG. Chidambaram R. Mueller RH. Waltermire RE. Org. Lett. 2008; 10: 5325
  CrossrefPubMedSearch in Google Scholar
• 7g Martin MT. Liu B. Cooley BE. Jr. Eaddy JF. Tetrahedron Lett. 2007; 48: 2555
  CrossrefSearch in Google Scholar
• 8a Chatani N. Hanafusa T. J. Org. Chem. 1986; 51: 4714
  CrossrefSearch in Google Scholar
• 8b Sundermeier M. Mutyala S. Zapf A. Spannenberg A. Beller M. J. Organomet. Chem. 2003; 684: 50
  CrossrefSearch in Google Scholar
• 9a Schareina T. Zapf A. Beller M. Chem. Commun. 2004; 1388
  PubMed
• 9b Weissman SA. Zewge D. Chen C. J. Org. Chem. 2005; 70: 1508
  CrossrefPubMedSearch in Google Scholar
• 9c Schareina T. Zapf A. Beller M. Tetrahedron Lett. 2005; 46: 2585
  CrossrefSearch in Google Scholar
• 9d Grossman O. Gelman D. Org. Lett. 2006; 8: 1189
  CrossrefPubMedSearch in Google Scholar
• 9e Schareina T. Zapf A. Mägerlein W. Müller N. Beller M. Tetrahedron Lett. 2007; 48: 1087
  CrossrefSearch in Google Scholar
• 10 Luo F.-H. Chu C.-I. Cheng C.-H. Organometallics 1998; 17: 1025
  CrossrefSearch in Google Scholar
• 11 Stewart TD. Fontana BJ. J. Am. Chem. Soc. 1940; 62: 3281
  CrossrefSearch in Google Scholar
• 12 Wen Q. Jin J. Hu B. Lu P. Wang Y. RSC Advances 2012; 2: 6167
  CrossrefSearch in Google Scholar
• 13 Jiang Z. Huang Q. Chen S. Long L. Zhou X. Adv. Synth. Catal. 2012; 354: 589
  CrossrefSearch in Google Scholar
• 14 Zhang Z. Liebeskind LS. Org. Lett. 2006; 8: 4331
  CrossrefPubMedSearch in Google Scholar
• 15 Sato N. Yue Q. Tetrahedron 2003; 59: 5831
  CrossrefSearch in Google Scholar
• 16 Anbarasan P. Neumann H. Beller M. Angew. Chem. Int. Ed. 2011; 50: 519 ; Angew. Chem.; 2011, 123, 539
  CrossrefPubMedSearch in Google Scholar
• 17 Kim J. Kim HJ. Chang S. Angew. Chem. Int. Ed. 2012; 51: 11949
  Search in Google Scholar
• 18 Wen QD. Lu P. Wang YG. Tetrahedron Lett. 2014; 55: 1271
  CrossrefSearch in Google Scholar
• 19a Zhang LP. Lu P. Wang YG. Chem. Commun. 2015; 2840
  PubMed
• 19b Zhang LP. Lu P. Wang YG. Org. Biomol. Chem. 2015; 13: 8322
  CrossrefPubMedSearch in Google Scholar
• 20 General Procedure for the Synthesis of α-Iminonitrile: t-Butyl isocyanide (1.5 mmol), iodobenzene (0.5 mmol), PdCl₂ (0.05 mmol), PCy₃ (0.1 mmol), Cs₂CO₃ (1.0 mmol), and 4 Å MS (100 mg) were added into a 15 mL sealed tube equipped with a magnetic stirring bar and stirred in DMF (2 mL) under argon at 135 °C for 18 h. After completion of the reaction as detected by TLC, it was poured into water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried (Na₂SO₄) and evaporated. The residue was purified on a silica gel column using petroleum ether/EtOAc as the eluent to give the pure target product. N-(tert-Butyl)benzimidoyl Cyanide: Yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.97 (m, 2 H), 7.52–7.40 (m, 3 H), 1.53 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 136.8 (s), 131.8 (s), 128.8 (s), 127.3 (s), 111.8 (s), 58.5 (s), 29.5 (s). HRMS (CI): m/z [M + H]⁺ calcd for C₁₂H₁₄N₂: 186.1157; found: 186.1154.
• 21 General Procedure for the Synthesis of the Cyanate Product: Aryl halide (0.5 mmol), α-iminonitrile (0.6 mmol), Cu(TFA)₂ (1.0 mmol), Pd(OAc)₂ (0.1 mmol) and DMF (2 mL)were added to a 15 mL sealed tube containing a magnetic stirring bar, and the mixture was stirred under air at 120 °C for 24 h (the progress of the reaction was monitored by TLC). The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was dried with Na₂SO₄, evaporated, and purified by by silica gel column chromatography. 4-Methoxy-benzonitrile (2a): See ref 19. White solid; mp 59–61 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.55 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 3.83 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 162.8 (s), 133.9 (s), 119.2 (s), 114.8 (s), 103.9 (s), 77.5 (s), 77.2 (s), 76.8 (s), 55.5 (s).

• Supplementary Material