Cu-mediated C–H cyanation of arenes using N,N-dimethylformamide (DMF) as the “CN” source

Abstract

This paper describes the direct C–H bond cyanation of 2-phenylpyridines employing N,N-dimethylformamide (DMF) as both the reagent and solvent. DMF provides both the C and N units in the generated “CN” group in this cyanation transformation. This reaction gives a novel protocol with high atom economy to extend the application of DMF and provides an alternative approach to aryl nitriles.

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Developing new methodologies with high atom economy¹ has been one of the most attractive goals in organic synthesis. In this context, scientists have recently developed lots of novel maneuvers to construct complex compounds from simple and readily available starting materials. Despite the fact that DMF has been widely used in organic synthesis as one of the popular polar solvents, the exploration of novel transformation of DMF, a versatile building block, has been significantly improved in the past few decades.²

Cyanation reaction is one of the important transformations due to the wide applications of the nitrile products in organic synthesis.^3–5 Traditionally, the transition-metal catalyzed cyanation reactions^6,7 often employ metal cyanides such as MCN (M = Cu, K, Na, Zn), TMSCN and K₃Fe(CN)₆ as the cyanating reagents, most of which are toxic and environmentally unfriendly. Very recently, a few of new organocyanating reagents were identified,⁶ such as nitromethane,^6a tosyl cyanide,^6e ethyl cyanoacetate,^6f isonitrile,^6g,o benzyl cyanide,^6h acetonitrile,^6i,k,n AIBN (2,2′-azobisisobutyronitrile)^6j and NCTS (N-cyano-N-phenyl-p-toluenesulfonamide).^6l,6m,6p

Significantly, elegant work has been reported by Chang and co-workers using DMF and ammonia or ammonium salts as the combined “CN” source to realize the cyanation of the carbon–hydrogen (heteroatom) bond (a, Scheme 1).⁸ Cheng et al. also realized the cyanation of aromatic halides by employing ammonium bicarbonate and DMF (or DMSO) as the combined “CN” source.⁹ In these reported cyanation reactions involving the combined “CN” source, DMF or DMSO provides the “C” unit of “CN”, while the “N” unit comes from ammonia or ammonium salts.^8,9

Scheme 1 DMF participates in different cyanation reactions.

Our group recently demonstrated a cyanation reaction of indoles by the direct C–H functionalization process (b, Scheme 1).¹⁰ To the best of our knowledge, this is the first and only report that DMF provides both the “C” and “N” units of the “CN” moiety in this cyanation reaction. However, the reaction is limited to indole substrates. Moreover, the reaction conditions are too complex. Besides the palladium catalyst, four kinds of other additives including Cu- and Fe-salts are required for this transformation. Thus, development of more concise systems to realize direct C–H cyanation with different substrates is still desirable. Herein, we described a direct C–H bond cyanation of pyridyl arenes using DMF alone as the source of “CN” (c, Scheme 1).

We initiated our study with 2-phenylpyridine (1a)¹¹ as a model substrate (Table 1). To our delight, when the reaction of 1a was conducted under O₂, the desired ortho cyanation product 2a was obtained in 10% yield in the presence of CuBr₂. The screening of copper salts showed that different copper species showed different efficiency in this cyanation reaction. Compared to CuBr₂, CuI, Cu(OTf)₂ and CuCN, the reaction with CuBr afforded the best result (entries 1–5, Table 1). Subsequently, the effects of different ligands were investigated (entries 6–8, Table 1). It was found that the reaction efficiency could be improved by adding 50 mol% of L1 (entry 6, Table 1). Attempts using other representive ligands which usually worked well with copper gave much lower yields (entries 7 and 8, Table 1). When a proton acid was added, such as acetic acid, the reaction was totally inhibited (entry 9, Table 1). Bases did not work either. The efficiency decreased drastically when TBD (1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine) or potassium bicarbonate was employed (entries 10 and 11, Table 1). When the equivalent of L1 declined to 25 mol%, the yield remained the same (entry 12, Table 1). Interestingly, when the reaction mixture was detected by GC-MS, we found that L1 decomposed to benzil (L4) under these conditions.¹² Consequently, benzil which is much cheaper than L1 was employed as the optimal ligand (entry 13, Table 1). However, lower yield was obtained when the loading of L4 was reduced to 10 mol% (entry 14, Table 1). Further studies indicate that O₂ is vital for the cyanation process due to the striking decrease in yields when the reactions were carried out under argon or air (entries 15 and 16, Table 1).

Table 1 Copper-mediated cyanation of 2-phenylpyridine^a

Entry	[Cu]	Ligand	Additive	Yield^b (%)
a Reaction conditions: 1a (0.4 mmol), DMF (3 mL), O2 (1 atm), 48 h. b Isolated yields. c 25 mol% of L4 was used. d 10 mol% of L4 was used. e The reaction was carried out under argon. f The reaction was carried out under air. TBD = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine.
1	CuBr2	—	—	10
2	CuI	—	—	38
3	Cu(OTf)2	—	—	Trace
4	CuCN	—	—	Trace
5	CuBr	—	—	43
6	CuBr	L1	—	61
7	CuBr	L2	—	Trace
8	CuBr	L3	—	Trace
9	CuBr	L1	AcOH	0
10	CuBr	L1	TBD	33
11	CuBr	L1	KHCO3	Trace
12^c	CuBr	L1	—	61
13	CuBr	L4	—	61
14^d	CuBr	L4	—	47
15^c^,^e	CuBr	L4	—	0
16^c^,^f	CuBr	L4	—	Trace

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With the optimal conditions in hand, we next investigated the substrate scope of this cyanation reaction (Table 2). Although many conditions have been screened, the reactions did not execute completely for some substrates. The remaining substrates could be recovered after the reactions. Products (2b–2f, 2h–2k) with different substituent groups on the phenyl rings were obtained in moderate yields. However, using methyl 4-(pyridin-2-yl)benzoate (1g) gave the desired product in poor yield. The sites of substituent groups on the phenyl ring did not affect the efficiency of this transformation (2h–2j). Substituted pyridyl (at the 3-position or 5-position) groups were also tolerant in this direct cyanation reaction (2l–2m). In addition, the substrates were also compatible with the optimal conditions when the pyridyl groups were substituted by fused aromatic rings (1n and 1q). It is noteworthy that 2-(naphthalen-2-yl)pyridine (1q) gave the products 2q and 2q′ as a mixture in 2.7 : 1 molar ratio. Meanwhile, a dicyanated product 2r was obtained in 12% yield. Furthermore, 1-phenylisoquinoline (1o) and benzo[h]quinoline (1p) worked smoothly under the optimized conditions to afford the desired products 2o and 2p in 35% and 44% yield, respectively.

Table 2 Copper-mediated cyanation of pyridyl arenes with DMF^a

a Standard reaction conditions: 1 (0.4 mmol), CuBr (0.8 mmol), DMF (3 mL), 135 °C, O₂ (1 atm), 48 h. Isolated yields. The number in the parentheses is the recovery of the substrates. b DMF (1 mL). c 0.2 mmol L1 instead of L4 was used.

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In order to probe the mechanism, some control experiments were investigated (Table 3). When the reaction was carried out in the presence of 2.0 equivalents of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), the efficiency of this transformation did not decrease (entry 1, Table 3), which might rule out a single electron transfer (SET) process. When N,N-dimethylacetamide (DMA) was used as the solvent instead of DMF, no cyanation product 2a was obtained (entry 2, Table 3). It is noteworthy that when CuCN which could provide the “CN” source was employed instead of CuBr in DMF, no expected product 2a was detected (entry 3, Table 3). This result indicates that the tandem processes including in situ formation of “CN” from DMF and the subsequent C–H cyanation step are not involved in this novel transformation.

Table 3 Mechanistic studies with the control reactions of 1a^a

Entry	Variation from the standard conditions	Yield^b (%)
a For the standard conditions, see entry 13, Table 1. b Isolated yields. c 1l was used instead of 1a. TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy, DMA = N,N-dimethylacetamide.
1	Additional TEMPO (2.0 eq.) was added	60
2	DMA instead of DMF	0
3	CuCN (2.0 eq.) instead of CuBr	0
4	Additional H2O (20.0 eq.) was added	59
5^c	Additional NH4I (1.2 eq.) was added	9

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Moreover, when additional water (20.0 eq.) was employed under the standard conditions, the reaction produced 2a in 59% yield (entry 4, Table 3), which demonstrates that water did not influence the reaction. Notably, the negative effect was obtained with only 9% yield when NH₄I (1.2 eq.), a crucial reagent in Chang's work,^8b–d was added under the standard conditions (entry 5, Table 3), which suggests that the mechanism of the present chemistry is totally different from that of Chang's reactions. However, the reaction mechanism is still not clear yet.

In conclusion, we have developed a novel Cu-mediated C–H bond cyanation reaction of arenes using the pyridyl group as a directing group. DMF provides both the “C” and “N” units in the generated “CN” group in this cyanation transformation. This reaction gives a novel protocol with high atom economy to extend the application of DMF and provides an alternative approach to prepare aryl nitriles.

Financial support from the National Science Foundation of China (no. 21325206, 21172006), the National Young Top-notch Talent Support Program, and the PhD. Programs Foundation of the Ministry of Education of China (no. 20120001110013) is greatly appreciated.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4qo00205a

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