Ni-Catalyzed Reductive Cross-Coupling of Amides with Aryl Iodide

Letter pubs.acs.org/OrgLett

Ni-Catalyzed Reductive Cross-Coupling of Amides with Aryl Iodide Electrophiles via C−N Bond Activation Shengyang Ni, Wenzhong Zhang, Haibo Mei, Jianlin Han,* and Yi Pan School of Chemistry and Chemical Engineering, State Key laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Nanjing University, Nanjing 210093, China S Supporting Information *

ABSTRACT: A Ni-catalyzed reductive cross-coupling reaction between two electrophiles, amides and aryl iodides, has been developed. This work is the first example using amide as an electrophile to couple with another electrophile, instead of using highly basic and pyrophoric nucleophiles. Furthermore, the Ni catalyst chemoselectively inserting the C−N bond of amide triggered the reductive cross-coupling reaction, which solves the problem that the Ni catalyst preferentially inserts the more reactive C−I bond to form a self-coupling product.

T

Scheme 1. Coupling Reaction via C−N Bond Activation of Amide

ransition-metal-catalyzed cross-coupling reactions for constructing the C−C bond have become one of the most versatile and powerful tools in modern organic chemistry.1 Among these transition-metal catalysts, nickel catalyst has occupies a very important position in the past because it is an environmentally friendly, naturally abundant, and inexpensive metal catalyst2g,h and also can easily switch among several oxidation states in catalytic cycles.2 In particular, Ni-catalyzed reductive cross-coupling has become one of the most active areas and has already witnessed a surge of development.3 Different from the traditional transition-metal-catalyzed coupling reaction between electrophiles and nucleophiles, it is the direct coupling of two electrophiles to simplify the procedure. The remarkable breakthrough has been reported by the Weix group on Ni/Pdcatalyzed cross-coupling of aryl bromides with aryl triflates in the presence of stoichiometric reducing reagent.4 Gong,5 Shi,6 and other groups7 have also developed elegant works in this field during the past two years. Amide is the most common structure existing in a broad range of organic molecules, natural products, agrochemicals, and pharmaceuticals.8 Furthermore, amide is an important organic synthetic intermediate. However, amide is known to be a poor electrophile, which is typically attributed to the resonance stability of the amide bond.9 Consequently, use of amides in C− N bond cleavage reactions remain limited. In 2015, efficient catalytic coupling systems via C−N bond activation of amides were established by Garg,10 Szostak,11 and others.12 These crosscoupling reactions usually used amides as electrophiles to couple with nucleophilic reagents, such as R−MgX, R−ZnX, R− B(OH)2, and so on10−13 (Scheme 1a). However, the direct coupling of amide with electrophiles has never been explored. Furthermore, these nucleophiles are usually unstable and sensitive to air and moisture. Sometimes, they may be much © 2017 American Chemical Society

more difficult to access, and the functional groups are usually limited to less reactive ones. Therefore, the development of new methods to alleviate some of these limitations in this field is still a highly desirable goal. In view of the above limitations, and inspired by the elegant works above,4,10−13 we considered that Ni-catalyzed reductive cross-coupling reaction of amide with electrophiles may be an alternative method in this area. We envisioned that the acyl metal intermediate Ni-A, generated from the insertion of Ni catalyst into the amide, could be oxidatively added by an aryl radical intermediate from aryl iodides (Ni−B, Scheme 1b). Herein, we Received: March 20, 2017 Published: May 5, 2017 2536

DOI: 10.1021/acs.orglett.7b00831 Org. Lett. 2017, 19, 2536−2539

Letter

Organic Letters

reaction with Ni catalyst, and this combination displayed high catalytic ability to affford an obviously increased yield (68%, entry 9). Finally, the yield could be further increased to 86% with the use of KF as additive (entry 15).4a After careful condition optimization, we focused on the investigation of different types of amide electrophiles (see Scheme S1 for details). Similar to the amide 1a, the amide 1b with two acyl groups also could work in this reaction to give a lower yield (65%). Using amides bearing benzyl (1c) and alkyl (1d, 1e), only a trace of the desired ketone product was detected due to the increased resonance effect of amides and making it more difficult for metal insertion into the C−N bond. Two tertbutyloxycarbonyl groups substituted on amide 1f could also work in this system with only 33% yield, which is consistent with metal insertion into the neutral amide C−N bond.10 Our next goal was to examine the substrate generality of these reducing cross-coupling reactions, and the results are summarized in Scheme 2.

report a Ni-catalyzed reductive cross-coupling reaction between amides and aryl iodides. This work is the first example of the use of amide as an electrophile to couple with another electrophiles, which can tolerated a wide scope of functional groups in excellent yields. To test this hypothesis, there are two problems that should be taken in consideration. The resonance effect of amides leads to their high bond-dissociation energy (BDE) of the C−N bond and makes activation difficult.14 Thus, the Ni catalyst may preferentially insert the more active C−I bond15 to form the selfcoupling product. The second question is whether the aryl radical could oxidatively add to acyl metal intermediate.4 Then, the envisioned NiI2-catalyzed reductive cross-coupling reaction of amide 1a was carried out with iodobenzene 2a as model electrophile in the presence of 2,2′-bipyridine ligand, and the representative results were given in Table 1 (see the SI for Table 1. Optimization of Reaction Conditionsa

Scheme 2. Substrate Scope Study of Ni-Catalyzed Reactiona,b

entry

ligand

metal

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

L1 L1 L1 L1 L1 L1 L1 L2 L3 L4 L5 L6 L7 L8 L3

Zn Mg Zn/Cu Zn Zn Zn Zn Zn Zn Zn Zn Zn Zn Zn Zn

additive

MgCl2 MgCl2/pyridinec NaId Bu4NIe

KF

yieldb (%) 51 trace 43 trace trace 22 34 45 68 34 18 58 50 trace 86

a

Reaction condition: amide 1a (0.2 mmol), iodobenzene 2a (1.5 equiv), NiI2 (10 mol %), ligand (10 mol %), reducing metal (2.0 equiv), and additive (1.0 equiv) in DMF (2 mL) under argon atmosphere for 12 h. bIsolated yields. cMgCl2 (1.0 equiv)/pyridine (1.0 equiv). d0.5 equiv. e0.5 equiv.

a

Reaction conditions: amide 1 (0.2 mmol), aryl iodides 2 (1.5 equiv), NiI2 (10 mol %), ligand (10 mol %), zinc metal (2.0 equiv), and KF (1.0 equiv) in DMF (2 mL) under argon atmosphere for 12 h. b Isolated yields. cReaction on 1 mmol scale.

details). Metal zinc has been demonstrated as the best reducing reagent in the current system and afforded the corresponding ketone product 3a with 51% yield (entry 1). The other reaction parameters, such as additives, were investigated (entries 4−7). However, no improvement was observed on the chemical yield, and only the phase-transfer catalyst could promote the reaction to give 34% yield (entry 7). Considering that 2,2′-bipyridine L1 was a bidentate nitrogen ligand with low steric hindrance, several substituted 2,2′-bipyridine derivatives were used for this reaction. The ligand L6, 2,2′-biquinoline, worked better in the current system and delivered the substrates to the ketone product with 58% yield (entry 12). Tridentate ligand showed the best inter-

As shown in Scheme 2, both starting aryl amide electrophiles 1 and aryl iodides electrophiles 2 can bear many electronwithdrawing and -donating groups in virtually all positions on the aromatic rings, affording the corresponding ketone product with up to 96% chemical yields (3a−y). Generally, electron-rich aryl iodide electrophiles (3b−g) are more reactive than electrondeficient ones (3h−l) and could react better with amide 1a. In the case of p-t-Bu-substituted aryl iodide, the reaction proceeded in excellent yield (3f, 96%), while aryl iodide bearing a ptrifluoromethyl group afforded a lower yield (3k, 64%). This 2537

DOI: 10.1021/acs.orglett.7b00831 Org. Lett. 2017, 19, 2536−2539

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Organic Letters

a Ni(0) catalyst, Ni(COD)2, was used. The reaction can provide the desired ketone product 3a in 16% yield and self-coupling product 7 (for details, see the SI). These results suggest clearly that the zinc acts as reducing reagent in the process. On the basis of the above results and previous reports,4−7 a possible mechanism, which contains C−N bond cleavage,10−12 radical oxidative addition, and reducing coupling key steps, is shown in Scheme 4 for this cross-coupling reaction of two

clearly indicates that the reaction proceeds through the aryl radical intermediate instead of arylzinc reagent. Remarkably, the reaction also tolerates naphthyl iodides (3n and 3o) and proceeds smoothly with good yields. Furthermore, we demonstrate that several substituted amides can also be successfully involved in these coupling reactions. Even the amide, containing a strong electron-withdrawing group (fluoro), could work very well in this reaction to give excellent yield (90%, 3y). Of particular importance is product 3p, obtained from the aliphatic amide, that outlines a greater generality of these previously unknown reducing coupling reactions. Finally, aryl iodides bearing cyano and acetyl groups were used in this reaction, and almost no desired products 3z and 3aa were obtained. To investigate the reaction mechanism, several control experiments were carried out (Scheme 3). First, a two-step

Scheme 4. Proposed Mechanism

Scheme 3. Control Experiments

electrophiles. Initially, the active Ni(0) catalyst generates from reduction of Ni(II), which inserts the C−N bond of amide 1a resulting in the Ni(II) complex A.4 Iodobenzene 2a reduced by reactive nickel(I) specie D results in the phenyl radical C, and C undergoes radical oxidative addition to Ni(II) complex A to afford the phenyl nickel(III) intermediate B.16 Reductive elimination of Ni(III) intermediate B forms the desired crosscoupling ketone product 3a as well as the reactive nickel(I) specie D. Such a Ni(I) complex D can be oxidized to amido Ni(II) iodide intermediate E by iodobenzene, which could be reduced by Zn power to regenerate the active Ni(0) catalyst for the next catalytic cycle.17 The generation of aryl radical C in the first catalytic cycle could occur by the reaction between Ni(II) intermediate A and iodobenzene 2a according to the general mechanism found in atom-transfer radical addition reactions.18 The catalytic cycle also may begin with Ni(0) species.19 The reaction could also proceed with the initial oxidative addition of ArI followed by nucleophilic acyl substitution. In summary, we developed an efficient Ni-catalyzed reductive cross-coupling reaction between amides and aryl iodides for the acyl−aryl C−C bond construction. This work is the first example use amide as an electrophile to couple with another electrophile under mild condition with zinc powder as a reducing agent. The reaction has been demonstrated to tolerate a broad substrate scope with regard to both the amide and aryl iodides, resulting in the corresponding ketone product with excellent yields. Preliminary control experiments appear to support preferential oxidative addition of aryl radical to acyl-Ni intermediate as the key step, which accounts for the chemoselective coupling of two carbon electrophiles. Studies to learn more details about the mechanism are underway in our laboratory.

reaction was performed with the filtering of zinc powder, and no corresponding ketone product 3a was obtained after 12 h (Scheme 3a). The reaction with the use of PhZnI has also been done, and no desired product 3a was detected (see the SI). These results reveal that the reaction does not proceed through an in situ generated organic zinc intermediate. A radical inhibition experiment was examined with addition of TEMPO (Scheme 3b). The reaction gave no desired product 3a, and only the TEMPO adduct acyl-TEMPO 4 was detected by ESI, which elucidates a radical pathway involved in this process. In addition, this ESI-MS result indicates that the benzyl acyl-Ni metal complex may be the intermediate and is consistent with the activation of the C−N bond of amide in Ni catalyst.10 Then a reaction was performed under the standard conditions with the addition of 1,1-diphenylethylene (DPE, 2.0 equiv) (Scheme 3c). The formation of product 3a was also suppressed, and the DPE coupling with phenyl radical products 5 and 6 was detected by GC−MS. This result indicates the current system is a radical process, and phenyl radical is the key intermediate in this reaction. To investigate the role of zinc, the reaction of 1a and 2a was conducted in the absence of zinc powder (for details, see the SI). When NiI2 was used, no 3a was detected, and the starting materials were remained (Scheme 3d). It is mainly because the Ni(II) species could not be converted into Ni(0) catalyst. Then, 2538

DOI: 10.1021/acs.orglett.7b00831 Org. Lett. 2017, 19, 2536−2539

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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.7b00831. Experimental procedures, full spectroscopic data for compounds 3, and 1H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jianlin Han: 0000-0002-3817-0764 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the National Natural Science Foundation of China (No. 21472082). Support from the Collaborative Innovation Center of Solid-State Lighting and Energy-Saving Electronics is also acknowledged.

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DOI: 10.1021/acs.orglett.7b00831 Org. Lett. 2017, 19, 2536−2539