Palladium-Catalyzed Reaction of Arylboronic Acids with Aliphatic Nitriles: Synthesis of Alkyl Aryl Ketones and 2-Arylbenzofurans

Abstract

An efficient palladium-catalyzed addition of arylboronic acids to aliphatic nitriles has been developed, providing a wide range of alkyl aryl ketones in moderate to excellent yields. It is noteworthy that sequential addition and intramolecular annulation reaction of 2-(2-hydroxyphenyl)acetonitriles with arylboronic acids are also conducted smoothly to afford 2-arylbenzofurans in good yields under the standard conditions.

Generally, the nitrile group is inert in organometallic reactions and thus acetonitrile or benzonitrile are usually used as solvents or ligands in many metal-catalyzed reactions. However, transformations of nitriles play an important role in both the laboratory and industry due to their well-recognized chemical versatility.[1] Transition-metal-catalyzed insertion of nitriles offers an attractive route for the creation of novel carbon–carbon and carbon–heteroatom bonds. Recently, a few examples of rhodium,[2] palladium,[3] and nickel-catalyzed[4] additions of arylboronic acids to nitriles became known; however, the substrate scope is usually limited to aromatic nitriles, and activated nitriles [e.g., cyanoformate[2b] and (benzyl-/arylsulfonyl)acetonitriles[2c]]. Compared to the reactions of aromatic nitriles, one of the main problems encountered in nucleophilic addition reactions of aliphatic nitriles is the insufficient electrophilic activation to perform the addition. On the other hand, aliphatic nitriles tend to be deprotonated in the presence of palladium catalysts leading to α-arylation products.[5] Thus, the addition reaction of aliphatic nitriles is generally more challenging than that of aromatic nitriles.

The insertions of nitrile groups by Grignard reagents[6] and organolithium reagents[7] are powerful tool for the construction of aryl ketones and heterocyclic compounds; however, the rigorous conditions have sometimes restricted their applications and the variety of substrates. Compared to the reactions using Grignard reagents and organolithium reagents, organoboron reagents are highly regarded due to their advantages of stability to air and moisture as well as good functional group tolerance.[8]

As part of the continuing efforts in our laboratory towards the development of novel transition metal-catalyzed reactions under participation of organoboron reagents,[9] we herein report a new method for the synthesis of alkyl aryl ketones by palladium-catalyzed addition of arylboronic acids to aliphatic nitriles (Scheme [1]). Furthermore, the scope of the developed approach is successfully explored toward one-step synthesis of 2-arylbenzofurans via sequential addition and intramolecular annulation reaction.

To optimize the reaction conditions, initial studies were concentrated on treatment of acetonitrile (1a) with phenylboronic acid (2a) as a model reaction. As shown in Table [1], the best result was observed with palladium(II) acetate as the catalyst in the presence of 2,2′-bipyridine (bpy) in this transformation (Table [1], entry 9). In contrast, the yield of the desired product 3a was decreased to some extent when the reactions were carried using other palladium sources in tetrahydrofuran (entries 1–7). On the other hand, the effect of solvents was also tested. Among all the solvents screened (e.g., THF, 1,4-dioxane, DMSO, DMF, toluene, and xylenes), tetrahydrofuran was determined to be the most effective medium for the generation of 3a (entries 9–14). Then, various acids were screened as the additive to examine their effect on the reaction. Screening revealed that various additives, including acetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid­, and benzoic acid were less effective than trifluoroacetic acid (entries 15–18). It was one of the major reasons that the use of trifluoroacetic acid as additive facilitates the generation of highly cationic [Pd(II)O₂CCF₃][10] species to form palladium–aryl complexes through transmetalation of arylboronic acids.

Table 1 Screening for Optimal Reaction Conditions^a

Entry	Pd source	Additive	Solvent	Yield (%)b
1	Pd(PPh3)4	CF3CO2H	THF	trace
2	Pd2(dba)3	CF3CO2H	THF	trace
3	Pd(dba)2	CF3CO2H	THF	trace
4	PdCl2(dppe)	CF3CO2H	THF	trace
5	PdCl2(PPh3)2	CF3CO2H	THF	trace
6	PdCl2	CF3CO2H	THF	trace
7	Pd(acac)2	CF3CO2H	THF	48
8	Pd(TFA)2	CF3CO2H	THF	83
9	Pd(OAc)2	CF3CO2H	THF	88
10	Pd(OAc)2	CF3CO2H	1,4-dioxane	71
11	Pd(OAc)2	CF3CO2H	DMSO	25
12	Pd(OAc)2	CF3CO2H	DMF	0
13	Pd(OAc)2	CF3CO2H	toluene	41
14	Pd(OAc)2	CF3CO2H	xylenes	37
15	Pd(OAc)2	CF3CO2H	THF	12
16	Pd(OAc)2	PhCO2H	THF	14
17	Pd(OAc)2	CF3SO3H	THF	72
18	Pd(OAc)2	4-MeC6H4SO3H	THF	42

^a Reaction conditions: 1a (0.4 mmol), 2a (0.8 mmol), Pd source (5 mol%), bpy (10 mol%), additive (10 equiv), solvent (2 mL), H₂O (0.4 mL), 80 °C, 36 h, N₂.

^b Isolated yield.

Having the optimized reaction conditions in hand, we explored the substrate scope of aliphatic nitriles and arylboronic acids for this transformation (Table [2]). Initially, the reaction between acetonitrile (1a) and various arylboronic acids 2b–j was investigated under the standard conditions (Table [2], entries 1–10). As shown in Table [2], the monosubstituent positions at the aryl moiety of arylboronic acids were evaluated, and the results demonstrated that steric effects of substituents affected the yields of the reaction to some extent. For example, the coupling of 1a with 4-, 3- and 2-tolylboronic acid was examined, 89% of 3b and 83% of 3c were isolated, while the yield of 3d was decreased to 51% (entries 2–4). In general, the arylboronic acids possessing electron-donating groups afforded a higher yield than electron-withdrawing arylboronic acids. For example, substrates 2e and 2f, bearing a 4-methoxyphenyl or 4-chlorophenyl group, reacted with substrate 1a to give the corresponding products in 93% and 75% yield, respectively (entries 5, 6). It is noteworthy that biarylboronic acids such as 4-phenylphenylboronic acid (2h), 1-naphthylboronic acid (2i), and 2-naphthylboronic acid (2j) also afforded the corresponding 3h, 3i, and 3j in 81%, 87%, and 82% yield, respectively (entries 8–10).

Table 2 Palladium-Catalyzed Synthesis of Alkyl Aryl Ketones^a

Entry	1	R	2	Ar	Product	Yield (%)b
1	1a	Me	2a	Ph	3a	88
2	1a	Me	2b	4-MeC6H4	3b	89
3	1a	Me	2c	3-MeC6H4	3c	83
4	1a	Me	2d	2-MeC6H4	3d	51
5	1a	Me	2e	4-MeOC6H4	3e	93
6	1a	Me	2f	4-ClC6H4	3f	75
7	1a	Me	2g	4-BrC6H4	3g	67
8	1a	Me	2h	4-PhC6H4	3h	81
9	1a	Me	2i	1-naphthyl	3i	87
10	1a	Me	2j	2-naphthyl	3j	82
11	1b	n-Bu	2a	Ph	3k	94
12	1c	n-C7H15	2a	Ph	3l	96
13	1d	i-Pr	2a	Ph	3m	84
14	1e	c-Pr	2a	Ph	3n	83
15	1f	Bn	2a	Ph	3o	97
16	1g	4-MeC6H4CH2	2a	Ph	3p	92
17	1h	4-O2NC6H4CH2	2a	Ph	3q	99
18	1i	2-HOC6H4CH2	2a	Ph	4a	94c

^a Unless otherwise noted, reaction conditions were as follows: 1 (0.4 mmol), 2 (0.8 mmol), Pd(OAc)₂ (5 mol%), bpy (10 mol%), TFA (10 equiv), THF (2 mL), H₂O (0.4 mL), 80 °C, 36 h, N₂.

^b Isolated yield.

^c 2-Phenylbenzofuran was obtained in 94% yield.

Subsequently, other aliphatic nitriles bearing α-alkyl substituents (e.g., 1b–e) or α-aryl substituents (e.g., 1f–i) were evaluated (Table [2], entries 11–18). The results disclosed that primary α-alkylnitriles, such as pentanenitrile (1b) and octanenitrile (1c), are suitable substrates, leading to the corresponding products in good yields (entries 11, 12). The transformation of secondary α-alkylnitriles, such as isobutyronitrile (1d) or cyclopropylnitrile (1e) with 2a also proceeded successfully to provide the respective products in 84% and 83% yield, respectively (entries 13, 14). Excellent yields were observed when α-aryl substituted nitriles 1f–h bearing either an electron-rich phenyl or electron-deficient phenyl group were used as substrate (entries 15–17). Interestingly, treatment of 2-(2-hydroxyphenyl)acetonitrile (1i) with 2a under the standard conditions afforded the unexpected 2-phenylbenzofuran (4a) in 94% yield instead of alkyl aryl ketone product (entry 18).

Benzofurans are abundant in numerous natural products and possess many important biological activities.[11] As an application of our chemistry, we next explored a simple and efficient approach to other 2-arylbenzofurans, which involves ketone formation from the addition of 2-hydroxyphenylacetonitriles with arylboronic acids, followed by intramolecular cyclization under mild conditions. As shown in Table [3], the electronic properties of the groups on the phenyl ring of arylboronic acids had some effect on the reaction. Electron-rich arylboronic acids with a methyl or methoxy group at the para position proved to be good substrates for this transformation, affording the corresponding 2-arylbenzofurans 4b and 4c in higher yields (Table [3], entries 2, 3). Having an electron-withdrawing substituent (e.g., fluoro, chloro, bromo, and phenyl) at the para position afforded a slightly lower yield of the desired products 4d–g (entries 4–7). Notably, the fluoro, chloro, and bromo moieties (commonly used for cross-coupling reactions) in arylboronic acids were all tolerated and afforded a novel route to compounds 4d–f in good yields, making further elaborations of the corresponding biarylbenzofuran derivatives possible.

Next, the addition reactions of several 2-hydroxyphenylacetonitriles with phenylboronic acid (2a) were investigated. As expected, the groups on the phenyl ring of 2-hydroxyphenylacetonitriles, such as methyl, chloro, bromo­, and methoxy, were quite compatible under the optimized reaction conditions. Generally, 2-hydroxyphenylacetonitriles having an electron-donating substituent (e.g., methyl and methoxy) on the phenyl group (Table [3], entries 8, 9) gave a slightly higher yield of the desired 2-arylbenzofurans than those analogues bearing electron-withdrawing substituent (e.g., chloro and bromo; entries 10, 11).

Table 3 Palladium-Catalyzed Synthesis of 2-Arylbenzofurans^a

Entry	1	R	2	Ar	Product	Yield (%)b
1	1i	H	2a	Ph	4a	94
2	1i	H	2b	4-MeC6H4	4b	91
3	1i	H	2e	4-MeOC6H4	4c	92
4	1i	H	2k	4-FC6H4	4d	86
5	1i	H	2f	4-ClC6H4	4e	84
6	1i	H	2g	4-BrC6H4	4f	81
7	1i	H	2h	4-PhC6H4	4g	85
8	1j	4-Me	2a	Ph	4h	91
9	1k	3-MeO	2a	Ph	4i	89
10	1l	4-Cl	2a	Ph	4j	81
11	1m	4-Br	2a	Ph	4k	80

^a Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), Pd(OAc)₂ (5 mol%), bpy (10 mol%), TFA (10 equiv), THF (2 mL), H₂O (0.4 mL), 80 °C, 36 h, N₂.

^b Isolated yield.

In summary, we have developed a new catalytic protocol to synthesize alkyl aryl ketones by palladium-catalyzed addition reaction of arylboronic acids with aliphatic nitriles in moderate to excellent yields. The scope of this chemistry is successfully explored toward one-step synthesis of 2-arylbenzofurans via sequential addition and intramolecular annulation reaction. Investigations on the further applications in the future for rapidly constructing other useful heterocyclic compounds are currently underway in our laboratory.

All chemicals were either purchased or purified by standard techniques. Melting points were measured on Digital Melting Point Apparatus WRS-1B and are uncorrected. ¹H NMR and ¹³C NMR spectra were recorded on a 500 MHz Bruker spectrometer (¹H 500 MHz and ¹³C 125 MHz), using CDCl₃ or DMSO-d ₆ as the solvent with TMS as the internal standard at r.t. Chemical shifts are given in δ relative to TMS, the coupling constants J are given in Hz. Column chromatography was performed using EM Silica gel 60 (300–400 mesh).

Alkyl Aryl Ketones 3 and 2-Arylbenzofurans 4; General Procedure

To a Schlenk tube with a magnetic stirring bar were charged the respective nitrile 1 (0.4 mmol), arylboronic acid 2 (0.8 mmol), Pd(OAc)₂ (5 mol%), bpy (10 mol%), TFA (10 equiv), THF (2 mL), and H₂O (0.4 mL) under N₂ atmosphere. The reaction mixture was stirred at 80 °C for 36 h. After cooling to r.t., the mixture was poured into EtOAc (5 mL), which was washed with sat. aq NaHCO₃ (2 × 10 mL) and then brine (1 × 10 mL). After extracting the aqueous layer with EtOAc (3 × 10 mL), the combined organic layers were dried (Na₂SO₄), and evaporated under vacuum. The residue was purified by flash column chromatography (hexane–EtOAc) to afford the desired products 3 or 4. All known compounds afforded analytical data identical to those reported literature previously (see Supporting Information for further details).

Acetophenone (3a)

Yield: 42.3 mg (88%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.96 (d, J = 7.1 Hz, 2 H), 7.57 (t, J = 7.4 Hz, 1 H), 7.47 (t, J = 7.4 Hz, 2 H), 2.61 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 198.2, 137.2, 133.1, 128.6, 128.3, 26.6.

2-Phenylbenzo[b]furan (4a)

Yield: 72.9 mg (94%); white solid; mp 119−120 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.86 (d, J = 7.4 Hz, 2 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.52 (d, J = 8.1 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 2 H), 7.34 (t, J = 7.4 Hz, 1 H), 7.28 (t, J = 7.6 Hz, 1 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.10 (s, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 156.0, 154.9, 130.5, 129.3, 128.8, 128.6, 125.0, 124.3, 123.0, 120.9, 111.2, 101.3.

Acknowledgment

We thank the National Natural Science Foundation of China (No. 21102105) and Natural Science Foundation of Zhejiang Province (No. LY12B02011) for financial support.

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• 2a Ueura K, Miyamura S, Satoh T, Miura M. J. Organomet. Chem. 2006; 691: 2821
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• 2b Shimizu H, Murakami M. Chem. Commun. 2007; 2855
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• 3b Zhou C, Larock RC. J. Org. Chem. 2006; 71: 3551
  CrossrefSearch in Google Scholar
• 3c Zhao B, Lu X. Tetrahedron Lett. 2006; 47: 6765
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• 3d Zhao B, Lu X. Org. Lett. 2006; 8: 5987
  CrossrefPubMedSearch in Google Scholar
• 3e Yu A, Li J, Cui M, Wu Y. Synlett 2007; 3063
  Thieme Connect
• 4 Wong YC, Parthasarathy K, Cheng CH. Org. Lett. 2010; 12: 1736
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• 5a Culkin DA, Hartwig JF. Acc. Chem. Res. 2003; 36: 234
  CrossrefSearch in Google Scholar
• 5b Culkin DA, Hartwig JF. J. Am. Chem. Soc. 2002; 124: 9330
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• 6a Jie S, Zhang S, Sun WH. Eur. J. Inorg. Chem. 2007; 5584
• 6b Ball SC, Davies RP, Raithby PR, Shields GP, Snaith R. J. Organomet. Chem. 1998; 550: 457
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• 6c Clegg W, Davies RP, Dunbar L, Feeder N, Liddle ST, Mulvey RE, Snaith R, Wheatley AE. H. Chem. Commun. 1999; 1401
• 7 Malamas MS, Erdei J, Gunawan I, Barnes K, Johnson M, Hui Y, Turner J, Hu Y, Wagner E, Fan K, Olland A, Bard J, Robichaud AJ. J. Med. Chem. 2009; 52: 6314
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• 8a Suzuki A. Acc. Chem. Res. 1982; 15: 178
  CrossrefSearch in Google Scholar
• 8b Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
  Search in Google Scholar
• 8c Suzuki A. J. Organomet. Chem. 1998; 576: 147
  Search in Google Scholar
• 9a Chen J, Peng Y, Liu M, Ding J, Su W, Wu H. Adv. Synth. Catal. 2012; 354: 2117
  CrossrefSearch in Google Scholar
• 9b Zhang J, Chen J, Liu M, Zheng X, Ding J, Wu H. Green Chem. 2012; 14: 912
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• 9c Lu W, Chen J, Liu M, Ding J, Gao W, Wu H. Org. Lett. 2011; 13: 6114
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• 9d Zheng X, Ding J, Chen J, Gao W, Liu M, Wu H. Org. Lett. 2011; 13: 1726
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• 9e Zheng H, Zhang Q, Chen J, Liu M, Cheng S, Ding J, Wu H, Su W. J. Org. Chem. 2009; 74: 943
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  Search in Google Scholar
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• Supplementary Material